Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl.N1C=CC=CC=1>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[S:26]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)=[CH:8][C:2]=1[F:1])(=[O:28])=[O:27]
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Reactant: CC1(C)OB(c2ccc(N)c(F)c2)OC1(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)OB(c2ccc(NS(=O)(=O)c3cc(Cl)ccc3Cl)c(F)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1.5 g of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline in 17 ml DCM and 0.5 ml pyridine, 1.5 g of 2,5-dichloro-benzenesulfonyl chloride were added, and the reaction mixture was stirred for 16 h at RT. Then the solvents were removed under reduced pressure and the crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/EtOAc. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 2.2 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH3:24])[C:12]2[N:13]=[C:14](S(C)(=O)=O)[N:15]=[CH:16][C:11]=2[CH:10]=1.C([NH:32][CH2:33][CH:34]1[O:38][C:37]2[CH:39]=[CH:40][C:41]([NH2:43])=[CH:42][C:36]=2[O:35]1)(OC(C)(C)C)=O>C(O)(=O)C>[NH2:32][CH2:33][CH:34]1[O:38][C:37]2[CH:39]=[CH:40][C:41]([NH:43][C:14]3[N:15]=[CH:16][C:11]4[CH:10]=[C:9]([C:3]5[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=5[Cl:8])[C:22](=[O:23])[N:21]([CH3:24])[C:12]=4[N:13]=3)=[CH:42][C:36]=2[O:35]1
Reactant: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(S(C)(=O)=O)nc21
Reactant: CC(C)(C)OC(=O)NCC1Oc2ccc(N)cc2O1
Solvent: CC(=O)O
Product: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(Nc3ccc4c(c3)OC(CN)O4)nc21

Procedure:
A mixture of 0.384 g of compound of formula (II), 6-(2,6-dichlorophenyl)-8-methyl-2-methylsulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one, and 0.266 g of compound of formula (III), (R/S)-2-(N-Boc-aminomethyl)-1,3-benzodioxol-5-ylamine, is heated in 4 ml of acetic acid at 80° C. for 2 h. The reaction medium is subsequently concentrated by half under vacuum, then taken up in water and ethyl acetate and brought to pH 6 with a saturated NaHCO3 solution; the organic phase is separated by settling, washed with water and then a saturated NaCl solution, dried over sodium sulfate and evaporated. The crude product obtained is purified by flash chromatography on silica with a gradient of 0 to 1% of methanol in dichloromethane. 0.252 g of expected product is obtained in the form of a yellow powder.
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.I[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([O:30][CH3:31])[CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(O)C>[CH3:31][O:30][C:26]1[CH:25]=[C:24]([C:8]2[CH:9]=[CH:10][C:5]([O:4][C@@H:3]([CH3:14])[C@H:2]([OH:1])[CH2:15][CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:6][CH:7]=2)[CH:29]=[CH:28][N:27]=1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
Reactant: COc1cc(I)ccn1
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: [Na+]
Solvent: CCO
Product: COc1cc(-c2ccc(O[C@@H](C)[C@H](O)CCc3cccnc3)cc2)ccn1
Temperature: 90 °C
Yield: 38 %

Procedure:
Prepared according to the method described in Example 21b) from (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.150 g, Example 21a), 4-iodo-2-methoxypyridine (0.235 g, Liebigs Annalen der Chemie (1992) Issue 9, 953-9), ethanol (3 ml), 2M aqueous sodium carbonate (0.5 ml) and tetrakis(triphenylphosphine)palladium(0) (0.025 g) with heating at 90° C. for 4 hours. After work up, the residue was purified by normal-phase HPLC, eluting with a gradient of 0-25% ethanol in dichloromethane to give the title compound as an oil (0.069 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]1.[C:18]1([N:24]2[C:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:27][C:26]([CH:35]=O)=[N:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH:17][CH2:35][C:26]2[CH:27]=[C:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:25]=2)[CH2:11][CH2:10]1
Reactant: O=Cc1cc(-c2ccccc2)n(-c2ccccc2)n1
Reactant: Cc1ccc(N2CCN(CCN)CC2)c(C)c1
Product: Cc1ccc(N2CCN(CCNCc3cc(-c4ccccc4)n(-c4ccccc4)n3)CC2)c(C)c1
Yield: 89.1 %

Procedure:
Compound 31 was prepared using the same method as that of Example 1 except that 4-(2,4-dimethylphenyl)piperazin-1-ylethylamine and 1,5-diphenylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([CH:22]3[CH2:24][CH2:23]3)=[O:21])[CH2:16][CH:15]2[CH2:25][OH:26])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:27]N(C=O)C.CI.[H-].[Na+]>C1COCC1.C([O-])(O)=O.[Na+]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([CH:22]3[CH2:23][CH2:24]3)=[O:21])[CH2:16][CH:15]2[CH2:25][O:26][CH3:27])(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N2CCN(C(=O)C3CC3)CC2CO)cc1
Reactant: CN(C)C=O
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COCC1CN(C(=O)C2CC2)CCN1S(=O)(=O)c1ccc(C(C)(C)C)cc1
Reaction time: 1 h

Procedure:
(1-(4-tert-Butylphenylsulfonyl)piperazin-2-yl)methanol (97 mg, 0.255 mmol, 1.0 equiv, prepared as described in example 17) was dissolved in 5 mL THF under N2 followed by the addition of 0.1 mL DMF, 0.079 mL methyl iodide (0.765 mmol, 3.0 equiv) and 18 mg sodium hydride (1.28 mmol, 5.0 equiv). The solution was allowed to stir for one hour, at which time the solution was diluted with a saturated NaHCO3 solution. The resulting solution was extracted (3×CH2Cl2), dried (Na2SO4), and concentrated under reduced pressure. Purification by flash chromatography (SiO2, 0.5-2% MeOH/CH2Cl2) gave the product as a white solid. 1H NMR (DMSO, 400 MHz) δ 7.79 (d, J=8.4 Hz, 2H), 7.63 (d, J=8.5 Hz, 2 H), 4.21-3.90 (m, 3 H), 3.65 (m, 1 H), 3.45-2.65 (m, 8 H), 1.82 (m, 1 H), 1.30 (s, 9 H), 0.683 (broad s, 4 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH2:13]O)[S:10][N:9]=2)=[CH:4][CH:3]=1.P(Br)(Br)[Br:16].O>C1(C)C=CC=CC=1>[Br:16][CH2:13][C:11]1[S:10][N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:12]=1
Reactant: OCc1nc(-c2ccc(Cl)cc2)ns1
Reactant: BrP(Br)Br
Solvent: O
Solvent: Cc1ccccc1
Product: Clc1ccc(-c2nsc(CBr)n2)cc1
Temperature: 120 °C
Yield: 75.3 %

Procedure:
To a solution of [3-(4-chlorophenyl)-[1,2,4]thiadiazol-5-yl]-methanol (0.25 g, 1.10 mmol) in toluene (8 ml) was added PBr3 (0.17 ml, 1.65 mmol). The resulting reaction mixture was refluxed at 120° C. for 15 min. After the completion of the reaction (TLC monitoring), the reaction mixture was cooled to 0° C., added water (50 ml) and extracted with ethyl acetate (3×50 ml). The combined organics was washed with saturated NaHCO3 solution, dried over Na2SO4, filtered and concentrated under vacuum. The crude residue was purified over silica gel (100-200 M, 2% EtOAc-Hexane) to get the desired product (0.24 g, 75%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([C:25]([O:27][CH3:28])=[O:26])=[C:9]([CH3:24])[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)=[N:11]2)=[CH:6][C:5]=1[S:29]([CH:32]([CH3:34])[CH3:33])(=[O:31])=[O:30])[CH3:2].[Br:35]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:35][CH2:24][C:9]1[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=2)=[N:11][C:12]2[C:7]([C:8]=1[C:25]([O:27][CH3:28])=[O:26])=[CH:6][C:5]([S:29]([CH:32]([CH3:33])[CH3:34])(=[O:31])=[O:30])=[C:4]([O:3][CH2:1][CH3:2])[CH:13]=2
Reactant: CCOc1cc2nc(-c3cccc(C(F)(F)F)c3)c(C)c(C(=O)OC)c2cc1S(=O)(=O)C(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOc1cc2nc(-c3cccc(C(F)(F)F)c3)c(CBr)c(C(=O)OC)c2cc1S(=O)(=O)C(C)C
Temperature: 100 °C

Procedure:
A suspension of methyl 7-(ethyloxy)-3-methyl-6-[(1-methylethyl)sulfonyl]-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (9.5 g, 19.17 mmol), N-bromosuccinimide (4.09 g, 23.01 mmol), and benzoyl peroxide (0.464 g, 1.917 mmol) in carbon tetrachloride (100 mL) was heated to reflux (100° C.) overnight. The reaction mixture was concentrated in vacuo to give methyl 3-(bromomethyl)-7-(ethyloxy)-6-[(1-methylethyl)sulfonyl]-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate. This material was used without further purification. MS (m/z) 576.0 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C@:8]2([CH3:15])[CH2:13][O:12][CH2:11][C:10]([NH2:14])=[N:9]2)[CH:7]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](Cl)([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:21][CH:20]=1>>[CH3:39][O:38][C:35]1[CH:34]=[CH:33][C:32]([C:25]([NH:14][C:10]2[CH2:11][O:12][CH2:13][C@:8]([C:6]3[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=3[F:16])([CH3:15])[N:9]=2)([C:22]2[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:37][CH:36]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: C[C@@]1(c2cc(Br)ccc2F)COCC(N)=N1
Product: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)COC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 72 %

Procedure:
In analogy to step c) in the synthesis of Building block I, the reaction of (R)-5-(5-bromo-2-fluoro-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine with 4,4′-dimethoxytriphenylmethyl chloride yielded the title compound as a white solid (72% of theory). Mass (calculated) C32H30BrFN2O3 [589.51]; (found) [M+H]+=589, [M+2-H]+=591.
Reaction SMILES: [C:1]([NH:4][C:5](=[CH2:10])[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2].[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.S([O-])([O-])(=O)=O.[Na+].[Na+]>ClCCl.[Fe](Cl)(Cl)Cl>[C:1]([NH:4][CH:5]([CH2:10][N:15]1[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]1)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2]
Reactant: CN1CCNCC1
Reactant: C=C(NC(C)=O)C(=O)OC
Agent: Cl[Fe](Cl)Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C(CN1CCN(C)CC1)NC(C)=O
Temperature: 20 °C
Reaction time: 66 h

Procedure:
To a solution of 8.57 g of methyl 2-acetamidoacrylate in 500 mL of dichloromethane stirred under inert atmosphere, about 6.65 mL of N-methylpiperazine are added, then 0.97 g of iron trichloride are added, and the mixture is stirred at a temperature of about 20° C. for 66 hours. Then, 300 mL of an aqueous solution of sodium sulfate are dropped to the reaction medium while stirring the reaction mixture and the mixture filtered through Celite. After separation of the phase by settling, the organic phase is dried over sodium sulfate, filtered and then concentrated in a vacuum oven under reduced pressure (2 kPa) at a temperature of about 40° C. in order to obtain an orange-colored liquid. The aqueous phase is extracted with 3 times 150 mL of dichloromethane and all of the organic extracts are collected, dried over sodium sulfate, then concentrated under reduced pressure (2 kPa) at a temperature of about 20° C. in order to obtain an yellow oil. Both of the organic extracts as described above are combined and purified by chromatography under argon pressure (50 kPa), on a column of silica gel (particle size 40–63 μm; diameter 5 cm; height 25 cm), eluting with successive mixtures of 20% dichloromethane/methanol/aqueous ammonia (99/1/0, 97/3/0, 90/10/0.25, 80/20/0.25 by volume). The fractions containing the expected product are combined and concentrated under reduced pressure (2 kPa) at a temperature of about 30° C. About 3.3 g of methyl 2-(acetylamino)-3-(4-methyl-piperazinyl)propanoate are obtained in the form of a yellow liquid. [Infrared spectrum CCl4 3437; 3318; 2941; 2798; 1749; 1685; 1499; 1458; 1374; 1286; 1204; 1168 and 1014 cm−1].
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[C:9]([Cl:17])[CH:8]=2)=[N:5][N:6]=1.[CH2:18]([C:20]1[C:25](/[CH:26]=[CH:27]/[O:28][CH3:29])=[CH:24][CH:23]=[CH:22][C:21]=1B1OC(C)(C)C(C)(C)O1)[CH3:19].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.O.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>[Cl:17][C:9]1[CH:8]=[C:7]([C:4]2[S:3][C:2]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25](/[CH:26]=[CH:27]/[O:28][CH3:29])[C:20]=3[CH2:18][CH3:19])=[N:6][N:5]=2)[CH:12]=[CH:11][C:10]=1[O:13][CH:14]([CH3:16])[CH3:15]
Reactant: CCc1c(/C=C/OC)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)Oc1ccc(-c2nnc(Br)s2)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1c(/C=C/OC)cccc1-c1nnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Temperature: 120 °C
Yield: 77.8 %

Procedure:
To a suspension of 2-bromo-5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazole (D10) (300 mg), 2-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (259 mg) and tripotassium phosphate (477 mg) in N,N-dimethylformamide (DMF) (8 mL) and water (2 mL) under nitrogen was added Pd(Ph3P)4 (104 mg). The reaction vessel was sealed and heated under microwave at 120° C. for 10 min. The reaction mixture was extracted with EA for 3 times, the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, the dried solution was concentrated, and purified by column chromatography to afford 2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-5-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-1,3,4-thiadiazole (D14) (290 mg) as a yellow oil. MS (ES): C22H23ClN2O2S requires 414. found 415.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][C:8]2[O:9][CH:10]=[C:11]([C:13]([OH:15])=O)[N:12]=2)=[CH:5][CH:4]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([C:28]2([CH2:33][NH:34]C(C3N=C(CC4C=CC(OC)=CC=4)SC=3)=O)[CH2:32][CH2:31][CH2:30][CH2:29]2)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([C:28]2([CH2:33][NH:34][C:13]([C:11]3[N:12]=[C:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:17][CH:16]=4)[O:9][CH:10]=3)=[O:15])[CH2:29][CH2:30][CH2:31][CH2:32]2)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: COc1ccc(Cc2nc(C(=O)NCC3(c4ccc(OC)c(OC)c4)CCCC3)cs2)cc1
Reactant: COc1ccc(Cc2nc(C(=O)O)co2)cc1
Product: COc1ccc(Cc2nc(C(=O)NCC3(c4ccc(OC)c(OC)c4)CCCC3)co2)cc1
Yield: 66 %

Procedure:
Starting from 2-(4-Methoxy-benzyl)-oxazole-4-carboxylic acid 25 g, 0.1 mmol) and [2-(3,4-Dimethoxy-phenyl)-2-methyl]-propylamine (47 mg, 0.2 mmol) following a similar procedure reported for the preparation of 2-(4-Methoxy-benzyl)-thiazole-4-carboxylic acid[1-(3,4-dimethoxy-phenyl)-cyclopentylmethyl]-amide, the amide (30 mg, 66%) was obtained as a white solid. ESI-MS m/Z calc. 450.5, found 451.2(M+1)+. Retention time of 3.51 minutes 1H NMR (400 MHz, CDCl3) δ1.68-2.19 (m, 8H), 3.50 (d, J=6.3 Hz, 2H), 3.81 (s, 3H), 3.88 (s, 3H), 3.92 (s, 3H), 4.00 (s, 2H), 6.73-6.88 (m, 6H), 7.20 (d, J=8.7 Hz, 2H), 8.07 (s, 1H).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[Cl:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:25]=1[Cl:26]>>[Cl:19][C:20]1[CH:21]=[C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)[CH:23]=[CH:24][C:25]=1[Cl:26]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Product: N#Cc1cc(-c2ccc(Cl)c(Cl)c2)c2c(c1)cc1n2CCCNC1=O

Procedure:
The title compound, off-white solid (80 mg, 86%), MS (ISP) m/z=370.4 [(M+H)+], mp 217.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available 3,4-dichloro-phenylboronic acid (62.0 mg, 0.325 mmol).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][N:5]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][C@@H:13]([C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])[CH2:12]2)[N:3]=1.[H][H]>C(O)C.[Pd]>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][N:5]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][C@@H:13]([C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])[CH2:12]2)[N:3]=1
Reactant: Nc1nc(N2CCO[C@@H](C(=O)N3CCCC3)C2)ncc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1cnc(N2CCO[C@@H](C(=O)N3CCCC3)C2)nc1N

Procedure:
To a solution of (R)-(4-(4-amino-5-nitropyrimidin-2-yl)morpholin-2-yl)(pyrrolidin-1-yl)methanone (0.15 g, 0.46 mmol) in ethanol (15 mL) was added 10% palladium-on-carbon (300 mg). The mixture was hydrogenated using a balloon filled with hydrogen gas at room temperature for 3 h. The mixture was filtered through a pad of Celite and the filtrate was used for the next step without further purification.
Reaction SMILES: [Mg].BrCCBr.Br[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[CH2:15][CH2:14]1.[C:16](=[O:18])=[O:17]>O1CCCC1>[CH:13]1([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:16]([OH:18])=[O:17])[CH2:15][CH2:14]1
Reactant: BrCCCCCCC1CC1
Reactant: O=C=O
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: O=C(O)CCCCCCC1CC1

Procedure:
0.684 g. Magnesium metal is covered with 2 ml. anhydrous tetrahydrofuran and 0.2 ml. 1,2-dibromoethane is added with stirring and heating. 1-Bromo-6-cyclopropylhexane (4.8 g.) and tetrahydrofuran (25 ml.) are added portionwise. An additional 0.207 ml. of 1,2-dibromethane is added and the reaction mixture refluxed for 3 hours. The solution is then maintained at 24°-28° while anhydrous carbon dioxide is bubbled through it for 11/2 hours. After stirring overnight under carbon dioxide, dry ether, water and 2N sulfuric acid are added until the pH is less than 7. The solution is extracted with ether and washed with water and brine, dried over calcium sulfate, filtered and the solvent removed to yield 7-cyclopropylheptanoic acid.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:6]=1[NH2:14].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([NH:22][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:6]=1[NH2:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: Nc1c(OCCCl)cccc1[N+](=O)[O-]
Product: Nc1c(OCCNCc2ccccc2)cccc1[N+](=O)[O-]
Temperature: 105 °C
Yield: 89.3 %

Procedure:
A mixture of 2-(2-chloro-ethoxy)-6nitro-phenylamine (1a, 3.0 g, 13.8 mmol) and benzylamine (9.0 g, 84.0 mmol) was heated neat at 100-110° C. for 6 hr. The excess benzylamine was removed by distillation under vacuum (70-75° C./0.1 mm). The residue was poured into 1 N sodium hydroxide (300 mL) and extracted with ethyl acetate (2×, 300 mL). The combined organic layer was washed with water (2×, 300 mL) and brine (300 mL). The ethyl acetate layer was dried over anhydrous magnesium sulfate, filtered, and the solvent removed under vacuum to give 5.1 g of crude red oil. Purification by chromatography (500 g silica gel, ethyl acetate: 2 M NH3 in methanol, 20:1) afforded 3.54 g (89.3%) of a red semi-solid, mp 33-60° C.; MS EI m/e 287 (M+).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH:52]=[CH:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[CH:46]([O:60][CH3:61])[CH2:45]2)[CH:7]([CH3:63])[CH2:6][CH2:5][C:4]1=[O:64])[CH3:2].[H][H]>[Rh]>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH2:52][CH2:53][C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)[CH:46]([O:60][CH3:61])[CH2:45]2)[CH:7]([CH3:63])[CH2:6][CH2:5][C:4]1=[O:64])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC=Cc4ccccc4)C(OC)C3)C(C)CCC1=O)C(C)CC2OC
Reactant: [H][H]
Agent: [Rh]
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCCCc4ccccc4)C(OC)C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.3 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(4"-cinnamyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (16 mg in 2 ml ethanol) was added 2 mg of 5% rhodium on carbon catalyst. The reaction flask was fitted with a hydrogen balloon, evacuated and recharged with hydrogen (3 times) and stirred at room temperature. After 30 minutes, the mixture was filtered over diatomacous earth, concentrated and purified by preparative TLC on silica gel (ethyl acetate: hexane (1:2)+1% methanol) to give the title compound (5.5 mg).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:13])[N:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[C:19]([O-])([O-])=O.[Na+].[Na+].IC>CN(C=O)C>[CH3:19][N:5]1[C:6]2[C:11](=[CH:10][C:9]([CH3:12])=[N:8][C:7]=2[CH3:13])[C:2](=[O:1])[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4]1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cnc2c(C)nc(C)cc2c1O
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C)c2c(C)nc(C)cc2c1=O
Temperature: 25 °C
Yield: 20.6 %

Procedure:
Ethyl 4-hydroxy-6,8-dimethyl-1,7-naphthyridine-3-carboxylate (Preparation 47, 460 mg) is dissolved in DMF (30 mL) and treated with Na2CO3 (396 mg). Iodomethane (0.3 mL) is slowly added to the mixture, and it is then heated to reflux for 1 h. The reaction mixture is cooled to room temperature, quenched with water (20 mL) and extracted with CH2Cl2 (50 mL). The organic layer is separated, dried (MgSO4), and to concentrated in vacuo. The residue is purified by silica gel column chromatography (5% methanol/CH2Cl2) to give 100 mg (21%) of the title compound as a white solid. Physical characteristics: MS (ESI+) m/z 261 (M+H)+; 1H NMR (DMSO) δ8.61, 7.78, 4.23, 4.18, 3.00, 2.56, 1.28.
Reaction SMILES: C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.[Br:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][CH:34]=[C:35]([C:40]([CH:42]2[CH2:44][CH2:43]2)=[O:41])[C:36]([O:38]C)=O)=[CH:29][C:28]=1[F:45]>>[Br:26][C:27]1[CH:32]=[C:31]2[C:30](=[CH:29][C:28]=1[F:45])[N:33]=[CH:34][C:35]([C:40]([CH:42]1[CH2:44][CH2:43]1)=[O:41])=[C:36]2[OH:38]
Reactant: COC(=O)C(=CNc1ccc(Br)c(F)c1)C(=O)C1CC1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=C(c1cnc2cc(F)c(Br)cc2c1O)C1CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.2 %

Procedure:
To Dowtherm at 250° C. was added methyl 3-(4-bromo-3-fluorophenylamino)-2-(cyclopropanecarbonyl)acrylate (7.5 g, 21.9 mmol) portionwise and the reaction mixture was stirred for 1.5 h. The reaction mixture was cooled to room temperature, diluted with hexanes and the resulting precipitate was filtered to afford the desired product (5.38 g, 79%) as a brown solid: ESI MS m/z 311 [C13H9BrFNO2+H]+.