Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([C:4]1[C:5]([CH2:13][CH3:14])=[N:6][CH:7]=[C:8]([CH:12]=1)[C:9]([OH:11])=O)[CH3:3].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:46]([C:48]1[CH:49]=[C:50]([CH:55]=[C:56]([CH3:59])[C:57]=1[OH:58])[C:51]([NH:53]O)=[NH:52])[CH3:47]>C(Cl)Cl>[CH2:2]([C:4]1[CH:12]=[C:8]([C:9]2[O:11][N:53]=[C:51]([C:50]3[CH:55]=[C:56]([CH3:59])[C:57]([OH:58])=[C:48]([CH2:46][CH3:47])[CH:49]=3)[N:52]=2)[CH:7]=[N:6][C:5]=1[CH2:13][CH3:14])[CH3:3]
Reactant: CCc1cc(C(=O)O)cnc1CC
Reactant: CCc1cc(C(=N)NO)cc(C)c1O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(-c2nc(-c3cc(C)c(O)c(CC)c3)no2)cnc1CC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 28.9 %

Procedure:
To a solution of 5,6-diethyl-nicotinic acid hydrochloride (920 mg, 4.3 mmol) and Hünig's base (2.76 g, 21 mmol) in DCM (50 mL) is added TBTU (1.785 g, 5.55 mmol) and the mixture is stirred at rt for 5 min. 3-Ethyl-4,N-dihydroxy-5-methyl-benzamidine (1.14 g, 4.7 mmol) is added and the mixture stirred for 0.5 h. The mixture is diluted with DCM, washed with sat. aq. NaHCO3 solution, dried over MgSO4, filtered and concentrated. The crude 5,6-diethyl-nicotinic acid (3-ethyl-4,N-dihydroxy-5-methyl-benzamidine) ester (LC-MS: tR=0.79 min) is dissolved in dioxane (50 mL) and heated to 100° C. for 18 h. The solvent is evaporated and the crude product is purified by FC on silica gel eluting with heptane:EA 10:1 to give 4-[5-(5,6-diethyl-pyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenol (0.42 g) as a solid; LC-MS: tR=1.03 min, [M+1]+=338.09.
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:9]=[N:8][C:7]([C:10]([OH:12])=O)=[CH:6][CH:5]=1)[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.CS(O)(=O)=O.[NH2:30][CH2:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[C:37](=[O:41])[N:36]([CH:42]1[CH2:47][CH2:46][C:45](=[O:48])[NH:44][C:43]1=[O:49])[C:35]2=[O:50].O>CN(C)C=O>[O:49]=[C:43]1[CH:42]([N:36]2[C:35](=[O:50])[C:34]3[C:38](=[CH:39][CH:40]=[C:32]([CH2:31][NH:30][C:10]([C:7]4[N:8]=[N:9][C:4]([S:3][CH2:1][CH3:2])=[CH:5][CH:6]=4)=[O:12])[CH:33]=3)[C:37]2=[O:41])[CH2:47][CH2:46][C:45](=[O:48])[NH:44]1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: CCSc1ccc(C(=O)O)nn1
Agent: CS(=O)(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1ccc(C(=O)NCc2ccc3c(c2)C(=O)N(C2CCC(=O)NC2=O)C3=O)nn1
Temperature: 40 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A stirred mixture of 6-ethylsulfanyl-pyridazine-3-carboxylic acid (0.37 g, 2.00 mmol) and CDI (0.36 g, 2.20 mmol) in N,N-dimethylformamide (20 mL) was heated to 40° C. under nitrogen. After 1 h, 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione methane sulfonate (0.77 g, 2.00 mmol) was added and the mixture was heated at 40° C. for 1.5 h. The mixture was cooled to rt and water (40 mL) was added. After 2 h, the product was isolated by filtration, washed with water (10 mL) and dried in vacuo to give 6-Ethylsulfanyl-pyridazine-3-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide as a white solid (0.78 g, 86% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 4.43 min (96.78%); mp: 205-207° C.; 1H NMR (DMSO-d6) δ 1.38 (t, J=7.3 Hz, 3H, CH3), 1.98-2.13 (m, 1H, CHH), 2.43-2.69 (m, 2H, CHH, CHH), 2.79-3.00 (m, 1H, CHH), 3.24-3.42 (m, 2H, CH2), 4.69 (d, J=6.2 Hz, 2H, CH—), 5.15 (dd, J=5.3, 12.8 Hz, 1H, CH), 7.75-7.93 (m, 4H, Ar), 7.97 (d, J=9.1 Hz, 1H, Ar), 9.98 (t, J=6.3 Hz, 5H, NH), 11.13 (s, 1H, NH); 13C NMR (DMSO-d6) δ 14.18, 21.99, 24.01, 30.93, 42.42, 48.99, 122.15, 123.53, 124.92, 126.89, 129.85, 131.57, 133.60, 147.19, 149.74, 162.99, 165.00, 166.97, 167.12, 169.82, 172.73; LCMS: MH=454; Anal Calcd for C21H19N5O5S: C, 55.62; H, 4.22; N, 15.44. Found: C, 55.43; H, 4.09; N, 15.22.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1Cl)=[O:13])[CH2:8]2.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CN1CCCC1=O>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1[N:25]1[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]1)=[O:13])[CH2:8]2
Reactant: Cn1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1Cl
Reactant: CN1CCNCC1
Solvent: CN1CCCC1=O
Product: CN1CCN(c2c(C(=O)NC3C4CC5CC(C4)CC3C5)cnn2C)CC1
Temperature: 25 °C
Yield: 57.3 %

Procedure:
A solution of 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Example 5, 59 mg; 0.20 mmol) and 1-methylpiperazine (0.47 mL; 4.2 mmol) in N-methylpyrrolidinone (0.8 mL) was heated to 230° C. in a sealed vial under microwave irradiation for 2 hr. The mixture was allowed to cool to room temperature and the crude product was purified by reverse phase HPLC to provide methyl-5-(4-methyl-piperazin-1-yl)-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (41 mg, 57%) as an off white solid. ES-HRMS m/e calcd for C20H32N5O (M+H+) 358.2602, found 358.2597.
Reaction SMILES: P(Br)(Br)[Br:2].[F:5][C:6]1[CH:7]=[C:8]2[C:13](=[C:14]([F:17])[C:15]=1[F:16])[N:12]=[CH:11][C:10]([CH2:18]O)=[C:9]2[C:20]1[S:21][CH:22]=[CH:23][CH:24]=1>C(Cl)Cl>[F:5][C:6]1[CH:7]=[C:8]2[C:13](=[C:14]([F:17])[C:15]=1[F:16])[N:12]=[CH:11][C:10]([CH2:18][Br:2])=[C:9]2[C:20]1[S:21][CH:22]=[CH:23][CH:24]=1
Reactant: OCc1cnc2c(F)c(F)c(F)cc2c1-c1cccs1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: Fc1cc2c(-c3cccs3)c(CBr)cnc2c(F)c1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 93.7 %

Procedure:
A solution of PBr3 (8.4 g, 31 mmol) in CH2Cl2 (40 ml) was added to the mixture of F13 (5.0 g, 15.5 mmol) in CH2Cl2 (30 ml) at 0° C. The resulting mixture was stirred for 10 minutes at 0° C. and then for 2 hour at room temperature before quenching with a saturated aqueous NaHCO3 solution to pH 8. The mixture was added to CH2Cl2 and the organic layer was separated, washed with water, dried over Na2SO4, and concentrated to obtain the title compound (5.2 g, 86.8%), mp: 98˜100° C. which was used without further purification.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:9]=3[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:18]1([O:23][C:24]2[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:18]1([O:23][C:24]2[CH:25]=[CH:26][C:27]([C:28]([C:11]3[S:10][C:9]4[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:8]=4[C:7]=3[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:29])=[CH:31][CH:32]=2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: COc1ccc2c(-c3ccccc3)csc2c1
Reactant: O=C(Cl)c1ccc(OC2CCCC2)cc1
Product: COc1ccc2c(-c3ccccc3)c(C(=O)c3ccc(OC4CCCC4)cc3)sc2c1

Procedure:
3-Phenyl-6-methoxybenzo[b]thiophene and p-cyclopentyloxybenzoyl chloride were converted to the title compound by the procedure of Example 1 to yield 6 g of crude product.
Reaction SMILES: C(OC(=O)[N:7]([CH3:25])[C:8]1[C:9]2[N:10]([C:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19](SC)[N:18]=3)=[CH:15][N:16]=2)[CH:11]=[CH:12][N:13]=1)(C)(C)C.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH3:25][NH:7][C:8]1[C:9]2[N:10]([C:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:18]=3)=[CH:15][N:16]=2)[CH:11]=[CH:12][N:13]=1
Reactant: CSc1nccc(-c2cnc3c(N(C)C(=O)OC(C)(C)C)nccn23)n1
Reactant: Nc1ccccc1
Product: CNc1nccn2c(-c3ccnc(Nc4ccccc4)n3)cnc12

Procedure:
Methyl-[3-(2-phenylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-amine was prepared by a process analogous to that described in Example 12 starting from methyl-[3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-carbamic acid tert-butyl ester (from Example 8 supra), and aniline. LC-MS: [M+H]+ 318.2.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]([CH3:18])[CH3:17])=[CH:13][CH:14]=3)[C:9]([S:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[C:8]2[CH2:24][C:25]([CH3:30])([CH3:29])[C:26](O)=[O:27])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]([CH3:18])[CH3:17])=[CH:13][CH:14]=3)[C:9]([S:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[C:8]2[CH2:24][C:25]([CH3:30])([CH3:29])[CH2:26][OH:27])=[CH:31][CH:32]=1
Reactant: CC(C)c1ccc2c(c1)c(SC(C)(C)C)c(CC(C)(C)C(=O)O)n2Cc1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)c1ccc2c(c1)c(SC(C)(C)C)c(CC(C)(C)CO)n2Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 200 mg of methyl 1-(p-chlorobenzyl) -3-(t-butylthio)-α,α-dimethyl -5-(i-propyl)-indole-2-propanoate (from Example 25) in 1.5 mL tetrahydrofuran (THF) was added 0.4 ml of a solution of lithium aluminum hydride (1.0M in THF) at 0° C. After 2 h at 0° C., the reaction mixture was quenched with saturated aqueous Na2SO4, diluted with ether and stirred at room temperature for 1 h. The resultant slurry was filtered and the filtrate concentrated to dryness. The resultant oil was purified by flash chromatography (eluant: hexane ethyl acetate, 8:2) to give the title compound as a viscous oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][C:16]2[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=2)=[C:6]([CH:14]=1)[C:7]([N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[O:8].C(N)(N)=[O:24].OO.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][C:16]2[C:17]([F:22])=[N+:18]([O-:24])[CH:19]=[CH:20][CH:21]=2)=[C:6]([C:7](=[O:8])[N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH:14]=1
Reactant: CCN(CC)C(=O)c1cc(Br)ccc1Oc1cccnc1F
Reactant: NC(N)=O
Agent: OO
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CCN(CC)C(=O)c1cc(Br)ccc1Oc1ccc[n+]([O-])c1F
Reaction time: 8 h

Procedure:
To a solution of 5-bromo-N,N-diethyl-2-(2-fluoropyridin-3-yloxy)benzamide (1.4 g, 3.81 mmol) and urea peroxide (1.076 g, 11.44 mmol) in 10 mL of DCM at 0 C was added dropwise trifluoroacetic anhydride (1.601 mL, 11.44 mmol) and the resulting reaction was stirred overnight. LCMS showed only less than 50% of desired conversion. The mixture was evaporated to dryness, quenched with Sat. NaHCO3, extracted with EA, dried over Na2SO4, filtered and evaporated to dryness. CC (DCM to DCM/EA=3:1 to DCM/MeOH=100:2 to 100:5 to 100:10) gave 3-(4-bromo-2-(diethylcarbamoyl)phenoxy)-2-fluoropyridine 1-oxide as an off white solid.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].Cl.[NH2:13][CH2:14][CH2:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1.C(N(CC)CC)C>ClCCl>[C:20]([C:19]1[CH:22]=[CH:23][C:16]([CH2:15][CH2:14][NH:13][C:2](=[O:3])[O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:17][CH:18]=1)#[N:21]
Reactant: N#Cc1ccc(CCN)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(CCNC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
With ice bath cooling, 5.82 ml (15.57 mmol) of benzyl chloroformate (45% in toluene) were added to a solution of 2.37 g (12.98 mmol) of 4-(2-aminoethyl)benzonitrile hydrochloride and 4.34 ml (31.14 mmol) of triethylamine in 95 ml of dichloromethane. The reaction mixture was stirred at room temperature overnight and then evaporated to dryness. The crude product obtained in this manner was purified by column chromatography on silica gel (mobile phase: petroleum ether/ethyl acetate 2:1 to 1:1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:5]([Cl:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:35]=[CH:34][C:25]2[NH:26][C:27](=[O:33])[CH2:28][CH2:29][C:30]([CH3:32])([CH3:31])[C:24]=2[CH:23]=1.Cl>O1CCOCC1.COCCO>[Cl:20][C:5]1[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[N:7][C:2]([NH:21][C:22]2[CH:35]=[CH:34][C:25]3[NH:26][C:27](=[O:33])[CH2:28][CH2:29][C:30]([CH3:32])([CH3:31])[C:24]=3[CH:23]=2)=[N:3][CH:4]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: CC1(C)CCC(=O)Nc2ccc(N)cc21
Agent: Cl
Solvent: C1COCCO1
Solvent: COCCO
Product: CC1(C)CCC(=O)Nc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)cc21
Temperature: 25 °C
Yield: 19 %

Procedure:
Combined N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (106 mg, 0.312 mmol), 7-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (77 mg, 0.377 mmol), 4 N HCl in dioxane (94 ul) and 2-methoxyethanol (3 mL). Heated reaction to 120° C. for 2 hours. Let reaction cool to room temperature and evaporated off solvent. Purified with normal phase chromatography to yield a white solid (30 mg, 19%), N-{(1R,2R)-2-[5-Chloro-2-(5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide. mp 170-185° C.; LCMS: m/z=507.33 (M+H+), 1H NMR (400 MHz, CDCl3) δ 7.84 (s, 1H), 7.58 (d, 1H, J=9.6 Hz), 7.30 (m, 4H), 6.87 (dd, 1H, J=8.6, 2.3 Hz), 5.79 (m, 1H), 3.80 (m, 1H), 3.27 (m, 1H), 2.78 (m, 3H), 2.31 (m, 2H), 2.13 (m, 4H), 1.78 (m, 2H), 1.36 (m, 10H).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[Cl:6][C:7]1[C:12](Cl)=[N:11][C:10]([C:14]#[N:15])=[C:9]([C:16]#[N:17])[N:8]=1.O.Cl>O1CCCC1>[C:1]([NH:5][C:12]1[C:7]([Cl:6])=[N:8][C:9]([C:16]#[N:17])=[C:10]([C:14]#[N:15])[N:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1nc(Cl)c(Cl)nc1C#N
Reactant: CC(C)(C)N
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)Nc1nc(C#N)c(C#N)nc1Cl
Reaction time: 0.5 h

Procedure:
t-Butylamine, 7.3 g (.1 mole), in 50 ml of dry tetrahydrofuran was added dropwise under nitrogen to a solution of 10 g (0.05 mole) of 2,3-dichloro-5,6-dicyanopyrazine in 100 ml of tetrahydrofuran. The rate of addition was controlled so that the reactants did not exotherm to greater than 35° C. When the addition was complete, the reactants were stirred an additional half hour and then poured into 1 l. of water. After adjusting the pH to 1-2 with 10% HCl, the precipitated product was filtered and washed thoroughly with water. Crude product after drying was twice recrystallized from 1-chlorobutane to give light yellow crystals having a mp of 169°-173° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][N:6]1[CH:14]=[N:13][C:12]2[C:11](=[O:15])[NH:10][C:9]([NH2:16])=[N:8][C:7]1=2.CN(C)C=O.[C:22](OC(=O)C)(=[O:24])[CH3:23]>N1C=CC=CC=1>[C:22]([O:1][CH2:2][CH2:3][O:4][CH2:5][N:6]1[CH:14]=[N:13][C:12]2[C:11](=[O:15])[NH:10][C:9]([NH2:16])=[N:8][C:7]1=2)(=[O:24])[CH3:23]
Reactant: Nc1nc2c(ncn2COCCO)c(=O)[nH]1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)OCCOCn1cnc2c(=O)[nH]c(N)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 9-(2-hydroxyethoxymethyl)guanine (4.6 g), dry dimethylformamide (46 ml), acetic anhydride (16 ml) and dry pyridine (24 ml) was stirred at room temperature overnight. The resulting white solid was removed by filtration and dissolved in warm dimethylformamide (100 ml), pyridine (10 ml) and acetic anhydride (8 ml) added and the mixture stirred for 18 hr. The white solid formed was removed by filtration, washed with ethyl acetate and recrystallized from dimethylformamide to give 9-(2-acetyloxyethoxymethyl)guanine (3.3 g), m.p. 240°-241° C.
Reaction SMILES: [CH2:1]([N:3]1[CH:8]=[CH:7][N:6]=[C:5](O)[C:4]1=[O:10])[CH3:2].P(Br)(Br)([Br:13])=O.C(=O)([O-])[O-].[Na+].[Na+].O>ClC(Cl)C>[Br:13][C:5]1[C:4](=[O:10])[N:3]([CH2:1][CH3:2])[CH:8]=[CH:7][N:6]=1
Reactant: O=P(Br)(Br)Br
Reactant: CCn1ccnc(O)c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(Cl)Cl
Product: CCn1ccnc(Br)c1=O
Temperature: 10 °C
Reaction time: 2 h
Yield: 40.1 %

Procedure:
10.5 g (75 mM) of 1-ethyl-3-hydroxypyrazine-2(1H)-one and 23.1 g (80.5 mM) of phosphorous oxybromide in 75 ml of dichloroethane were refluxed under stirring for 2 h. The reaction mixture was then neutralized to pH 7-8 with a saturated aqueous solution of sodium carbonate, while maintaining the temperature at 10° C. The reaction mixture was then stirred at room temperature for 1 h. Water was added and the organic phase was extracted with dichloromethane. The combined organic layer was washed with water, dried on anhydrous sodium sulfate and the solvent was removed under vacuum. The compound was further purified by silica gel column chromatography using dichloromethane as eluant to give 6.1 g of 3-bromo-1-ethylpyrazin-2(1H)-one as a solid.
Reaction SMILES: Cl[CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[NH:5][CH2:4]1.[N-:9]=[N+:10]=[N-:11].[Na+].[N-]=[N+]=[N-].C([N+](CCCC)(CCCC)CCCC)CCC>CC(C)=O.CN(C)C=O>[N:9]([CH2:2][C@H:3]1[O:7][C:6](=[O:8])[NH:5][CH2:4]1)=[N+:10]=[N-:11]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1NC[C@H](CCl)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@@H]1CNC(=O)O1

Procedure:
5-(R)-Chloromethyloxazolidine-2-one (prepared according to [Danielmeier et al. Efficient Pathways to (R)- and (S)-hydroxymethyl-2-oxazolidinone and some derivatives. Tetrahedron: Asymmetry. 1995, vol. 6, pp. 1181-1190] (5 mmol) is reacted with sodium azide (7-10 mmol) in acetone (ca. 40-50 mL) at r.t for ca, 24 h (until the reaction is completed). Solids are filtered off, and supernatant evaporated under vacuum to afford the product which is immediately used for the next step. Optionally, the synthesis is performed in dry N,N-dimethylformamide under inert atmosphere with sodium azide (5-10 mmol) or tetrabutylammonium azide (5-10 mmol), and the resulting solution of the crude 5-(S)-azidomethyloxazolidine-2-one is employed for the next step without solvent removal.
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[N-].[CH3:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([CH:18]=[C:19]([C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=3)[N:20]=2)[CH:17]=1>C1(C)C=CC=CC=1.[Cu]>[C:7]([O:6][C:4]([CH2:3][C:18]1[N:16]2[CH:17]=[C:12]([CH3:11])[CH:13]=[CH:14][C:15]2=[N:20][C:19]=1[C:21]1[CH:22]=[CH:23][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:29][CH:30]=1)=[O:5])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)C=[N+]=[N-]
Reactant: COC(=O)c1ccc(-c2cn3cc(C)ccc3n2)cc1
Agent: [Cu]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2nc3ccc(C)cn3c2CC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Yield: 46.8 %

Procedure:
Tert-butyl diazoacetate (5 ml, 35.15 mmol) then copper powder (2.5 g) were gradually added to a refluxing solution of 9 (5.0 g, 18.8 mmol) in anhydrous toluene (150 ml). After a further 3 h of reflux, the mixture was cooled to room temperature, the suspension filtered and dried. Purification by column chromatography on silica gel (ethyl acetate-hexane, 1:1) gave methyl 4-(3-tert-butoxycarbonylmethyl-6-methylimidazo[1,2-a]pyridin-2-yl)benzoate 10 (3.35 g, 47%).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:35]([C@@H:37]([O:39]C(=O)C)[CH3:38])=[O:36]>>[OH:39][C@@H:37]([CH3:38])[C:35]([N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:36]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: O=C(NC1CCNCC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Agent: Cl
Product: C[C@H](O)C(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from 4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A138) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:8][C:9]1[CH:10]=[C:11]([OH:23])[CH:12]=[C:13]([C:15]2([O:21][CH3:22])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[F:8][C:9]1[CH:10]=[C:11]([CH:12]=[C:13]([C:15]2([O:21][CH3:22])[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[CH:14]=1)[O:23][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: COC1(c2cc(O)cc(F)c2)CCOCC1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc(F)cc(C2(OC)CCOCC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.9 %

Procedure:
A mixture of ethyl bromoacetate (0.5 g, 3 mmol), 3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenol (Example 8, Step 4) (0.3 g, 1.3 mmol) and K2CO3 (0.11 g, 0.8 mmol) in dimethylformamide (5.0 mL) was stirred at room temperature for 16 h under an argon atmosphere. The reaction mixture was partitioned between 5% citric acid (25 mL) and EtOAc (25 mL). The organic phase was washed with water, dried (Na2SO4), filtered and concentrated. The resulting syrup was purified by flash column chromatography on silica gel, eluting with 25% EtOAc in hexane, to give 0.3 g (73%) of ethyl 3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenoxyacetate as a colorless viscous liquid: 1H NMR (CDCl3/300 MHz) δ 6.77 (d, 2H, J=10.5 Hz), 6.52 (d, 1H, J=10.5 Hz), 4.61 (s, 2H), 4.28 (q, 2H, J=6.9 Hz), 3.82 (m, 4H), 2.99 (s, 3H), 1.92 (m, 4H), 1.31 (t, 3H, J=6.9 Hz). FABMS m/z=313 (M+H). HRMS calcd for C16H22FO5 313.1451, found 313.1399.
Reaction SMILES: O1CCCC1.C([O:8][C:9]([CH:11]([C:24]#[C:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:12][NH:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][N:15]=1)=O)C.[CH3:32][NH2:33]>CO>[CH3:32][NH:33][C:9]([CH:11]([C:24]#[C:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:12][NH:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][N:15]=1)=[O:8]
Reactant: CN
Reactant: CCOC(=O)C(C#Cc1ccccc1)CNc1ncnc2ccccc12
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)C(C#Cc1ccccc1)CNc1ncnc2ccccc12
Temperature: 60 °C
Reaction time: 24 h

Procedure:
To 5 ml of tetrahydrofuran were added 130 mg of 4-[2-ethoxycarbonyl-4-phenyl-3-butynylamino]quinazoline and 3 ml of a 40% solution of methylamine in methanol, and the mixture was stirred at 60° C. for an hour, then at room temperature for 24 hours. The reaction mixture was concentrated and purified by means of flash chromatography (Isolera™ manufactured by Biotage AB) to give 113 mg of 4-[2-methylaminocarbonyl-4-phenyl-3-butynylamino]quinazoline.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[C:5]([C:9]1[CH2:13][CH2:12][C:11](=O)[CH:10]=1)([CH3:8])([CH3:7])[CH3:6].Cl>C(OCC)C>[CH2:1]([C:12]1[CH2:11][CH:10]=[C:9]([C:5]([CH3:8])([CH3:7])[CH3:6])[CH:13]=1)[CH3:2]
Reactant: CC[Mg]Br
Reactant: CC(C)(C)C1=CC(=O)CC1
Agent: Cl
Solvent: CCOCC
Product: CCC1=CC(C(C)(C)C)=CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 104.2 %

Procedure:
A 300-ml three-necked flask equipped with a magnetic stirrer and a three-way cock in a nitrogen atmosphere was charged with 200 ml of dehydrated diethyl ether and 52 ml of a 3.0 M diethyl ether solution of ethylmagnesium bromide (154 mmol). In an ice water bath, 17.8 g (129 mmol) of 3-tert-butylcyclopentenone was added dropwise to the flack over a period of 1 hour. The mixture was stirred at room temperature for 20 hours, and the resultant reaction solution was poured into 100 ml of 2N hydrochloric acid. The organic phase was separated, and the aqueous phase was extracted with 50 ml of ether two times. The organic phases were combined and washed two times with a saturated aqueous sodium hydrogencarbonate solution, two times with water, and two times with a saturated salt solution. The product was dried over magnesium sulfate and the solvent was distilled off. The distillate was purified by column chromatography to give 20.2 g of a light yellow transparent liquid (GC purity: 75%). The yield was 78%. The compound was identified by 1H-NMR spectroscopy. The results are as follows.