Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[N:7]([CH3:8])[CH:6]([CH3:9])[CH2:5][N:4]([C:10]2[CH:20]=[CH:19][C:13]([C:14]([O:16]CC)=O)=[CH:12][CH:11]=2)[CH2:3]1.[NH2:21][C:22]1[N:26](C(OC(C)(C)C)=O)[N:25]=[C:24]([CH2:34][CH2:35][C:36]2[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[C:38]([O:44][CH3:45])[CH:37]=2)[CH:23]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH3:43][O:42][C:40]1[CH:41]=[C:36]([CH2:35][CH2:34][C:24]2[NH:25][N:26]=[C:22]([NH:21][C:14](=[O:16])[C:13]3[CH:12]=[CH:11][C:10]([N:4]4[CH2:5][CH:6]([CH3:9])[N:7]([CH3:8])[CH:2]([CH3:1])[CH2:3]4)=[CH:20][CH:19]=3)[CH:23]=2)[CH:37]=[C:38]([O:44][CH3:45])[CH:39]=1
Reactant: COc1cc(CCc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Reactant: CCOC(=O)c1ccc(N2CC(C)N(C)C(C)C2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(CCc2cc(NC(=O)c3ccc(N4CC(C)N(C)C(C)C4)cc3)n[nH]2)cc(OC)c1
Yield: 7.4 %

Procedure:
N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-(3,4,5-trimethylpiperazin-1-yl)benzamide was prepared following the procedure as for Example 94, but starting from ethyl 4-(3,4,5-trimethylpiperazin-1-yl)benzoate (310 mg, 0.86 mmol), tert-butyl 5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate (225 mg, 0.65 mmol) and 1M NaHMDS (2.59 ml, 2.59 mmol) in THF (5 ml). The crude product was purified by reverse phase prep. HPLC (basic) using a 38-58% gradient of acetonitrile in water containing 1% 0.880 ammonia. The clean fractions were taken and evaporated to afford the title compound as a white solid (23 mg, 5.6%); 1H NMR (399.99 MHz, CDCl3) δ1.09 (6H, d), 2.17-2.28 (2H, m), 2.22 (3H, s), 2.56 (2H, t), 2.81-2.90 (4H, m), 3.48 (2H, d), 3.68 (6H, s), 6.22 (1H, t), 6.28 (2H, s), 6.56 (1H, s), 6.78 (2H, d), 7.68 (2H, d0, 8.86 (1H, s), 9.65 (1H, s). MS: m/z 464 (MH+).
Reaction SMILES: [CH:1]1[C:6]([C:7]2[C:16](=[O:17])[C:15]3[C:14]([OH:18])=[CH:13][C:12]([O:19][C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)=[CH:11][C:10]=3[O:9][CH:8]=2)=[CH:5][CH:4]=[C:3]([OH:31])[CH:2]=1>Cl>[CH:5]1[C:6]([C:7]2[C:16](=[O:17])[C:15]3[C:14]([OH:18])=[CH:13][C:12]([OH:19])=[CH:11][C:10]=3[O:9][CH:8]=2)=[CH:1][CH:2]=[C:3]([OH:31])[CH:4]=1
Reactant: O=c1c(-c2ccc(O)cc2)coc2cc(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)cc(O)c12
Agent: Cl
Product: O=c1c(-c2ccc(O)cc2)coc2cc(O)cc(O)c12
Yield: 74.8 %

Procedure:
About 49.0 mg of genistin were refluxed in 15 ml 4N HCl for five hours at 105°±5° C. About 22.9 mg of genistein was obtained with about 75% recovery. About 13 mg genistein from the previous step was extracted twice with 50 ml diethyl ether. The extracts were combined, and evaporated to dryness. The solids obtained were crystallized from 2 ml of a solution made from 3 parts ethanol and 2 parts water. About 8.2 mg of the genistein crystal was obtained with 63% recovery and about 99% purity.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH2:8].[Cl:9][CH:10](Cl)C.C=O>O>[ClH:9].[S:1]1[C:2]2[CH2:6][CH2:7][NH:8][CH2:10][C:3]=2[CH:4]=[CH:5]1
Reactant: NCCc1cccs1
Reactant: CC(Cl)Cl
Agent: C=O
Solvent: O
Product: Cl
Product: c1cc2c(s1)CCNC2
Temperature: 30 °C
Reaction time: 0.08 h
Yield: 90 %

Procedure:
100 gm. of 2-thienylethylamine was charged in a 1 liter reaction vessel equipped with a dean stark assembly for azeotropic removal of water. Dichloroethane (600 ml.) was added and the mixture stirred for 5 minutes. 26.4 gm. paraformaldehyde was added and the reaction mass was heated to reflux. Water formed in the reaction was continuously removed. After 4 hours the reaction mass was cooled to 30° C. and 133 ml. of 6.6N hydrochloric acid solution in dimethyl formamide was added. The reaction mass was heated to 70° C. for 4 hours. The reaction cooled to 15° C. and filtered under suction and washed with dichloroethane. The solid obtained was dried in oven at 50° C. 124 gm (90%) of 4,5,6,7-tetrahydrothieno(3,2-c)pyridine hydrochloride are obtained.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH2:11])[CH:4]=[CH:3][CH:2]=1.[Cl:12][C:13]1[C:18]([C:19](O)=[O:20])=[C:17]([F:22])[C:16]([CH2:23][NH:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:15][CH:14]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:12][C:13]1[C:18]([C:19]([NH:11][C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[N:1]=[CH:2][CH:3]=[CH:4]3)=[O:20])=[C:17]([F:22])[C:16]([CH2:23][NH:24][C:25](=[O:30])[C:26]([CH3:28])([CH3:27])[CH3:29])=[CH:15][CH:14]=1
Reactant: Nc1cccc2cccnc12
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3cccnc23)c1F
Yield: 10.7 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using quinolin-8-amine (Intermediate-48, 50 mg, 0.34 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 119 mg, 0.41 mmol), oxalyl chloride (78 mg, 0.62 mmol), DMF (1 drop) and DIPEA (132 mg, 1.02 mmol) in CH2Cl2 (5 mL) to afford 15 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.73 (s, 1H), 8.91 (s, 1H), 8.71 (d, J=8.1 Hz, 1H), 8.48 (d, 1H), 8.16 (t, 1H), 7.78 (d, 1H), 7.67 (t, J=7.2 Hz, 2H), 7.40 (m, 2H), 4.32 (d, 2H), 1.14 (s, 9H); MS (m/z): 414.23 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]#[N:21])=[C:7]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH:18]=O)[CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1.[N:22]1([CH2:27][CH2:28][NH2:29])[CH2:26][CH2:25][CH2:24][CH2:23]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]#[N:21])=[C:7]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH2:18][NH:29][CH2:28][CH2:27][N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)[CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1c(-c2cncc(C=O)c2)c(C#N)c2ccc(Cl)cc21
Reactant: NCCN1CCCC1
Product: Cn1c(-c2cncc(CNCCN3CCCC3)c2)c(C#N)c2ccc(Cl)cc21

Procedure:
6-Chloro-2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile (Example 126) and 2-pyrrolidin-1-yl-ethylamine are processed according to the method described in Example 170 to give 6-chloro-1-methyl-2-{5-[(2-pyrrolidin-1-yl-ethylamino)-methyl]-pyridin-3-yl}-1H-indole-3-carbonitrile. The free base is taken up in 4M HCl in dioxane, concentrated in vacuo, dissolved in water and lyophilized to give the HCl salt. 1H NMR (400 MHz, DMSO-d6) δ ppm (HCl salt) 1.83-1.93 (m, 2H), 2.04 (br. s., 2H), 3.06 (br. s., 2H), 3.50 (br. s., 2H), 3.54-3.60 (m, 2H), 3.66 (br. s., 2H), 3.84 (s, 3H), 4.43 (br. s., 2H), 7.39 (dd, J=8.6, 1.8 Hz, 1H), 7.75 (d, J=8.3 Hz, 1H), 8.01 (d, J=1.5 Hz, 1H), 8.43 (t, J=2.0 Hz, 1H), 8.94 (d, J=2.0 Hz, 1H), 8.99 (d, J=2.0 Hz, 1H), 9.97 (br. s., 2H), 10.89 (br. s., 1H). HRMS (ESI) m/z 394.1803 [(M+H)+ Calcd for C22H25ClN5: 394.1798].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:16][CH:15]=1)[S:9]([CH3:12])(=[O:11])=[O:10].[CH3:35][I:36]>>[I-:36].[CH3:35][N+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]([S:9]([CH3:12])(=[O:11])=[O:10])[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:18][CH:19]=1
Reactant: CCCCCCCCCCCCCCOc1ccc(CN(Cc2ccccn2)S(C)(=O)=O)cc1
Reactant: CI
Product: CCCCCCCCCCCCCCOc1ccc(CN(Cc2cccc[n+]2C)S(C)(=O)=O)cc1
Product: [I-]
Temperature: 90 °C
Reaction time: 23 h
Yield: 99.6 %

Procedure:
A mixture of 0.350 g of product from Example 122 and 5.08 g of methyl iodide is heated at 90° C. for 17 hours. Thin layer chromatography shows the presence of starting material. The mixture is reheated at 125° C. for 23 hours. The reaction is concentrated in vacuo to give 0.45 g of the desired product as pale yellow crystals.
Reaction SMILES: Cl.N1([C:8]2[C:13]([F:14])=[CH:12][C:11]([N:15]3[CH2:19][C@H:18]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[O:17][C:16]3=[O:25])=[CH:10][C:9]=2[F:26])CCC=CC1.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[CH3:33][C:34]1([CH3:42])[O:38][C@H:37]([C:39](Cl)=[O:40])[CH2:36][O:35]1.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:33][C:34]1([CH3:42])[O:38][C@H:37]([C:39]([N:27]2[CH2:32][CH2:31][C:30]([C:8]3[C:9]([F:26])=[CH:10][C:11]([N:15]4[CH2:19][C@H:18]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:12][C:13]=3[F:14])=[CH:29][CH2:28]2)=[O:40])[CH2:36][O:35]1
Reactant: CC1(C)OC[C@@H](C(=O)Cl)O1
Reactant: c1ccncc1
Reactant: CC(=O)OC[C@H]1CN(c2cc(F)c(N3CC=CCC3)c(F)c2)C(=O)O1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OC[C@H]1CN(c2cc(F)c(C3=CCN(C(=O)[C@@H]4COC(C)(C)O4)CC3)c(F)c2)C(=O)O1
Reaction time: 3 h
Yield: 97.7 %

Procedure:
3-(4-(1,2,5,6-tetrahydropyridyl)-3,5-difluorophenyl)-5(R)-acetoxymethyloxazolidin-2-one hydrochloride (14.5 g, 37.3 mM) was suspended in dry dichloromethane (300 ml) under nitrogen at 0°, and treated with pyridine (9.78 g, 0.12 M). A solution of 2,2-dimethyl-1,3-dioxolan-4(S)-ylcarbonyl chloride (9.59 g, 75.6 mM) in dichloromethane (100 ml) was added dropwise, and stirring continued for 3 hours, allowing the temperature to rise to ambient. Aqueous sodium bicarbonate (5%, 300 ml) was added, and stirring continued for 30 minutes. The organic phase was separated, dried (magnesium sulfate), filtered, and evaporated to dryness after the addition of toluene (20 ml). The solid residue was triturated with a mixture of diethyl ether (250 ml) and isohexane (150 ml), and solid filtered to give the title compound (17.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:20])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-:22].[Na+].BrCC(=O)[CH2:29][C:30]1C=CC=C[C:31]=1[O:36][C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=3)[CH2:29][C:30]([OH:22])([CH2:31][O:36][C:37]3[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=3)[N:20]=2)=[CH:6][CH:7]=1
Reactant: O=C(CBr)Cc1ccccc1Oc1ccc(Cl)cc1
Reactant: O=C([O-])O
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2ccc(Cl)cc2)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: CS(=O)(=O)c1ccc(N2CC(O)(COc3ccc(Cl)cc3)N=C2c2ccc(Cl)cc2)cc1
Yield: 35.5 %

Procedure:
To a mixture of 4-chloro-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide (Example 1, Step 1) (1 g, 3.24 mmol) and sodium bicarbonate (550 mg, 6.5 mmol) in acetone (100 mL), 1-bromo-3-[(4-chlorophenoxy)phenyl]-2-propanone from Step 2 (1.5 g, 5.8 mmol) was added. After heating to reflux for 24 hours, the reaction mixture was filtered, washed with acetone and concentrated in vacuo. The crude mixture (2.5 g) was purified by chromatography (silica gel, toluene/ethyl acetate, 1/1) to give 2-(4-chlorophenyl)-4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-[(4-chlorophenoxy)methyl]-4,5-dihydro-1H-imidazole (565 mg, 35%) as a white solid.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:29]([CH2:30][CH2:31][CH2:32][CH2:33][C:34](O)=[O:35])=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:37](=[O:48])[NH:38][C@@H:39]([C:41]4[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=4)[CH3:40])[CH:26]=3)[C:21]2=[O:49])=[CH:16][CH:15]=1.C1CCN2C(=NCCC2)CC1.[CH:61]1([S:64]([NH2:67])(=[O:66])=[O:65])[CH2:63][CH2:62]1>O1CCCC1>[CH:61]1([S:64]([NH:67][C:34](=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][C:29]2[N:20]([C:17]3[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=3)[C:21](=[O:49])[C:22]3[C:27]([CH:28]=2)=[CH:26][C:25]([C:37]([NH:38][C@@H:39]([C:41]2[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=2)[CH3:40])=[O:48])=[CH:24][CH:23]=3)(=[O:66])=[O:65])[CH2:63][CH2:62]1
Reactant: NS(=O)(=O)C1CC1
Reactant: C[C@@H](NC(=O)c1ccc2c(=O)n(-c3ccc(F)cc3)c(CCCCC(=O)O)cc2c1)c1ccc(F)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)c1ccc2c(=O)n(-c3ccc(F)cc3)c(CCCCC(=O)NS(=O)(=O)C3CC3)cc2c1)c1ccc(F)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 47.9 %

Procedure:
CDI (13.50 mg, 0.083 mmol) was added to a stirred, room temperature mixture of (R)-5-(2-(4-fluorophenyl)-6-((1-(4-fluorophenyl)ethyl)carbamoyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoic acid (28 mg, 0.055 mmol) in tetrahydrofuran (2 mL) and the mixture was stirred at 70° C. for 2 h. DBU (0.017 mL, 0.111 mmol) and cyclopropylsulfonamide (10.09 mg, 0.083 mmol) were added, the resultant mixture was kept stirring at room temperature overnight. The mixture was concentrated, and the residue was purified via PTLC (Emerck 1 mm), eluted with CH2Cl2/MeOH=10:1 to give (R)-3-(5-(cyclopropanesulfonamido)-5-oxopentyl)-2-(4-fluorophenyl)-N-(1-(4-fluorophenyl)ethyl)-1-oxo-1,2-dihydroisoquinoline-6-carboxamide (16 mg) as a white solid. LCMS [M+H]+=608. 1H NMR (500 MHz, DMSO) δ ppm: 9.06 (d, J=7.88 Hz, 1H), 8.20 (d, J=8.20 Hz, 1H), 8.15 (s, 1H), 7.36-7.50 (m, 6H), 7.18 (t, J=8.99 Hz, 2H), 6.69 (s, 1H), 5.22 (t, J=7.25 Hz, 1H), 3.16-3.19 (m, 1H), 2.87-2.94 (m, 1H), 2.26 (br. s, 2H), 2.16 (br. s, 2H), 1.51 (d, J=7.25 Hz, 3H), 1.43 (br. s, 3H), 0.98-1.05 (m, 4H).
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH:6]1[O:10][CH:9]([CH2:11][OH:12])[CH2:8][CH2:7]1)[CH:2]=[CH2:3].Cl[CH2:14][C:15]([N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])=[O:16].[H-].[Na+].O>CS(C)=O>[CH2:18]([N:17]([CH2:21][CH2:22][CH3:23])[C:15](=[O:16])[CH2:14][O:12][CH2:11][CH:9]1[CH2:8][CH2:7][CH:6]([CH2:5][O:4][CH2:1][CH:2]=[CH2:3])[O:10]1)[CH2:19][CH3:20]
Reactant: C=CCOCC1CCC(CO)O1
Reactant: CCCN(CCC)C(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C=CCOCC1CCC(COCC(=O)N(CCC)CCC)O1
Temperature: 25 °C
Yield: 141 %

Procedure:
A mixture of 6.89 g of tetrahydro-5-[(2-propenyloxy)methyl]-2-furanmethanol (0.04 mole) and 7.12 g of 2-chloro-N,N-dipropylacetamide (0.02 mole) are dissolved in 200 ml of dry dimethyl sulfoxide and the mixture stirred at room temperature under nitrogen. Slowly, 0.50 g of sodium hydride (0.02 mole) is added to the dimethyl sulfoxide mixture and the reaction allowed to stir at ambient temperature (23°). After stirring for 10 minutes an exothermic reaction begins to take place and an ice-bath is used to maintain the reaction temperature below 30°. After stirring for 1 hour, the ice-bath is removed and the reaction allowed to stir at room temperature for 18 hours. The excess NaH is destroyed by adding 5 ml of methanol and the entire reaction mixture is then poured into 400 ml of water. The product is extracted with 3×125 ml portions of chloroform. The CHCl3 extracts are combined and washed with 4×300 ml portions of water. The CHCl3 layer is separated and dried over anhydrous Na2SO4 overnight. The CHCl3 is removed in vacuo yielding a pale yellow oil which is vacuum distilled and the fraction distilling at 185°-188° @ 0.5 mm is collected yielding 8.84 g (70%) of the above compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([NH:40][C:41]2[CH:49]=[C:48](B3OC(C)(C)C(C)(C)O3)[CH:47]=[C:46]3[C:42]=2[CH:43]=[CH:44][N:45]3[CH2:59][O:60][CH2:61][CH2:62][Si:63]([CH3:66])([CH3:65])[CH3:64])(=[O:39])=[O:38])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:48]2[CH:47]=[C:46]3[C:42]([CH:43]=[CH:44][N:45]3[CH2:59][O:60][CH2:61][CH2:62][Si:63]([CH3:66])([CH3:65])[CH3:64])=[C:41]([NH:40][S:37]([C:34]3[CH:33]=[CH:32][C:31]([O:30][CH3:29])=[CH:36][CH:35]=3)(=[O:39])=[O:38])[CH:49]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: COc1ccc(S(=O)(=O)Nc2cc(B3OC(C)(C)C(C)(C)O3)cc3c2ccn3COCC[Si](C)(C)C)cc1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(S(=O)(=O)Nc2cc(-c3c(N)ncnc3N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)cc3c2ccn3COCC[Si](C)(C)C)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 63.1 %

Procedure:
A solution of (S)-2-(1-((6-amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.23 mmol) were added 4-methoxy-N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-4-yl)benzenesulfonamide (194 mg, 0.30 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (18 mg, 0.02 mmol) and 227 μl of a 2M aqueous solution of cesium carbonate in dioxane (2 ml). The mixture was stirred under argon atmosphere at 100° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude was purified using SP1® Purification System (0% to 75%, hexane-ethyl acetate) to obtain 115 mg (60% yield) of the title compound as a white solid. Purity 95%.
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][CH:4]([CH:6]1[S:10][CH2:9][CH:8](O)[CH:7]1[N+:12]([O-:14])=[O:13])[CH3:5].S(Cl)(C)(=O)=O.C(N(CC)CC)C.O>ClCCl>[CH3:1][CH:2]([CH3:15])[CH2:3][CH:4]([CH:6]1[C:7]([N+:12]([O-:14])=[O:13])=[CH:8][CH2:9][S:10]1)[CH3:5]
Reactant: CC(C)CC(C)C1SCC(O)C1[N+](=O)[O-]
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CC(C)C1SCC=C1[N+](=O)[O-]
Reaction time: 7.5 h
Yield: 47.7 %

Procedure:
After dissolving 0.50 g of 5-(4-methylpentan-2-yl)-4-nitrotetrahydrothiophen-3-ol in 4 ml of dichloromethane, 0.27 g of mesyl chloride and 0.33 g of triethylamine were gradually dropped thereto at 4° C. The temperature of the solution was allowed to rise to room temperature, and the solution was stirred for 7.5 hours. Water was added to stop the reaction, and the solution was extracted with dichloromethane. The organic layer was dried with magnesium sulfate and concentrated, and then purified by silica gel chromatography (hexane/ethyl acetate=10/1), thereby obtaining 0.22 g of 2-(4-methylpentan-2-yl)-3-nitro-2,5-dihydrothiophene (yield: 47.7%).
Reaction SMILES: C(O[CH:6](N(C)C)[N:7]([CH3:9])[CH3:8])(C)(C)C.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[C:21]2[C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[C:33]([N+:38]([O-:40])=[O:39])[CH:32]=2)=[CH:16][CH:15]=1>CN(C=O)C>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[C:21]2[C:31]2[CH:36]=[CH:35][C:34](/[CH:37]=[CH:6]/[N:7]([CH3:9])[CH3:8])=[C:33]([N+:38]([O-:40])=[O:39])[CH:32]=2)=[CH:16][CH:15]=1
Reactant: Cc1ccc(-c2nc3ccccc3c(=O)n2-c2ccc(Cl)cc2)cc1[N+](=O)[O-]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: CN(C)C=O
Product: CN(C)/C=C/c1ccc(-c2nc3ccccc3c(=O)n2-c2ccc(Cl)cc2)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
tert-butoxybis(dimethylamino)methane (0.50 mL, 2.30 mmol) was added to a solution of 3-(4-chlorophenyl)-2-(4-methyl-3-nitrophenyl)quinazolin-4(3H)-one (0.300 g, 0.76 mmol) in DMF (20 mL). Stirring at 50° C. for 3 hours and concentrating in vacuo afforded (E)-3-(4-chlorophenyl)-2-(4-(2-(dimethylamino)vinyl)-3-nitrophenyl)quinazolin-4(3H)-one (0.340 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)=[CH:4][C:3]=1[O:17][CH2:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:26].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH2:41]([N:43]([CH2:47][CH3:48])[CH2:44][CH2:45][NH2:46])[CH3:42]>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([NH:46][CH2:45][CH2:44][N:43]([CH2:47][CH3:48])[CH2:41][CH3:42])=[O:14])=[CH:15][CH:16]=2)=[CH:4][C:3]=1[O:17][CH2:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:26]
Reactant: Nc1ncc(-c2ccc(C(=O)O)cc2)cc1OCc1c(Cl)cccc1Cl
Reactant: CCN(CC)CCN
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCN(CC)CCNC(=O)c1ccc(-c2cnc(N)c(OCc3c(Cl)cccc3Cl)c2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 71 %

Procedure:
To a solution of 4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-benzoic acid (50 mg, 0.13 mmol), HOBT (21 mg, 0.156 mmol), and EDC (30 mg, 0.156 mmol) in DMF (2 mL) was added N,N-diethylethylenediamine (0.022 mL, 0.156 mmol). The reaction was stirred at room temperature for 24 hr, then diluted with EtOAc, and partitioned with H2O. The organic was separated and the aqueous was extracted with EtOAc. The organic layers were combined, washed with saturated NaHCO3, and concentrated to dryness under vacuum. The material was purified using column chromatography (silica gel, 99:1 to 95:5 CH2Cl2/MeOH) to give 4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-N-(2-diethylamino-ethyl)-benzamide (45 mg, 72% yield) as a white solid.
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH3:7])[C:3](Cl)=[O:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:19]([O:26][C:27](=[O:30])[CH2:28][NH2:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[CH2:19]([O:26][C:27](=[O:30])[CH2:28][NH:29][C:3](=[O:4])[CH:2]([Br:1])[CH2:6][CH3:7])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCC(=O)OCc1ccccc1
Reactant: CCC(Br)C(=O)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(Br)C(=O)NCC(=O)OCc1ccccc1

Procedure:
65.96 g (355.7 mmol) of α-bromobutyric acid chloride is added in drops at 0° C. to 100 g (296.4 mmol) of glycine benzyl ester p-toluenesulfonic acid salt and 89.98 g (889.2 mmol) of triethylamine in 500 ml of methylene chloride. In this case, the temperature remains between 0° C.-5° C. 1000 ml of 5% aqueous hydrochloric acid is added, and the organic phase is separated.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@@H:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:7][CH2:6]1)=O.O.[NH2:19][NH2:20]>C(O)CCC>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[O:11][C@@H:8]1[CH2:9][CH2:10][C@H:5]([C:3]([NH:19][NH2:20])=[O:2])[CH2:6][CH2:7]1
Reactant: COC(=O)[C@H]1CC[C@@H](Oc2ccccn2)CC1
Reactant: NN
Solvent: O
Solvent: CCCCO
Product: NNC(=O)[C@H]1CC[C@@H](Oc2ccccn2)CC1
Temperature: 125 °C

Procedure:
A mixture of cis-4-(pyridin-2-yloxy)-cyclohexanecarboxylic acid methyl ester (0.39 g, 1.6 mmol) and hydrazine hydrate (0.40 ml, 8.2 mmol) in n-butanol (0.5 ml) was heated at 125° C. over night. After cooling to room temperature the reaction mixture was partitioned between dichloromethane (75 ml) and water (75 ml). The aqueous layer was washed with dichloromethane/75 ml). The combined organic layers were washed with water (75 ml) and brine (75 ml), dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude title compound (0.35 g, 91%) as colorless oil, which was used in the next step without further purification. MS m/e: 236 (M+H+)