Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[NH:4][N:5]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[C:6](=[O:22])[C:7]=1[N:8]=[N:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([S:17](O)(=[O:19])=[O:18])=[CH:12][C:11]=1[CH3:21])#[N:2].C(#N)C.P(Cl)(Cl)([Cl:35])=O>CN(C)C(=O)C>[Cl:35][S:17]([C:13]1[C:14]([CH3:16])=[CH:15][C:10]([N:9]=[N:8][C:7]2[C:6](=[O:22])[N:5]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])[NH:4][C:3]=2[C:1]#[N:2])=[C:11]([CH3:21])[CH:12]=1)(=[O:19])=[O:18]
Reactant: Cc1cc(S(=O)(=O)O)c(C)cc1N=Nc1c(C#N)[nH]n(-c2ccccc2C)c1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Solvent: CC(=O)N(C)C
Product: Cc1cc(S(=O)(=O)Cl)c(C)cc1N=Nc1c(C#N)[nH]n(-c2ccccc2C)c1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
8.6 g of the azo obtained in step (2) above, 35 ml of acetonitrile, and 8.6 ml of N,N-dimethylacetamide were put into a 100 ml three-necked flask and 8.6 ml of phosphorus oxychloride was added dropwise to the mixture at a temperature of 50° C. or below. After completion of the dropwise addition, the mixture was stirred for 30 minutes and then poured into ice water. The crystals thus deposited were collected by filtration.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][C:11]([CH3:15])([CH3:14])[CH2:10][O:9]2)=[CH:4][CH:3]=1.[Mg].[CH2:17](Br)[CH:18]=[CH2:19]>C1COCC1>[CH2:19]([C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][C:11]([CH3:15])([CH3:14])[CH2:10][O:9]2)=[CH:4][CH:3]=1)[CH:18]=[CH2:17]
Reactant: C=CCBr
Reactant: CC1(C)COC(c2ccc(Br)cc2)OC1
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CCc1ccc(C2OCC(C)(C)CO2)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 58.9 %

Procedure:
In a dry apparatus a solution of 12 (2.05 g, 7.60 mmol) in THF (15 mL) was added dropwise to magnesium powder (0.22 g, 9.1 mmol) under argon. After the addition was completed the mixture was refluxed for 45 min. Then the mixture was cooled to rt and allyl bromide (720 μL, 8.30 mmol) dissolved in THF (10 mL) was added slowly. The mixture was stirred for 4.5 h, then quenched with satd aq NH4Cl (25 mL) and extracted with ether. The combined organic phases were washed with aq NaHCO3 (5%) and brine and dried (Na2SO4). The solvents were removed under reduced pressure and the residue was crystallized from hexanes and filtered. The filtrate was purified by column chromatography (silica, ether/hexanes, 1:4), affording a light yellow oil (1.04 g, 59%). IR (neat): {tilde over (v)} 3077, 2955, 2904, 2846, 1639, 1619, 1517; 1H NMR δ 0.79 (s, 3H), 1.29 (s, 3H), 3.38 (d, 3J=6.6 Hz, 2H), 3.64 (d, 2J=11.0 Hz, 2H), 3.76 (d, 2J=11.0 Hz, 2H), 5.00-5.10 (m, 2H), 5.37 (s, 1H), 5.86-6.01 (m, 1H), 7.19, 7.43 (AA′BB′, 2×2H); 13C NMR (APT) δ 21.7 (−), 22.9 (−), 30.0 (+), 39.8 (+), 77.5 (+), 101.5 (−), 115.6 (+), 126.1 (−), 128.4 (−), 136.3 (+), 137.2 (−), 140.5 (+); GC-MS (EI) obsd 232, 231, 191, 163, 145, 115, 105, 91, 69, 56, 41; Anal. Calcd for C15H20O2: C, 77.55; H, 8.68. Found: C, 77.52; H, 8.77.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].[CH3:15][C:16]1[O:22]C(C)(C)O[C:18](=[O:19])[CH:17]=1>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:18]([O:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14])(=[O:19])[CH2:17][C:16]([CH3:15])=[O:22]
Reactant: O=C1c2ccccc2C(=O)N1CCO
Reactant: CC1=CC(=O)OC(C)(C)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)OCCN1C(=O)c2ccccc2C1=O
Yield: 76.4 %

Procedure:
A solution of 10.0 g (52.3 mmol) of N-(2-hydroxyethyl)phthalimide, 8.84 ml (67.7 mmol) of 2,2,6-trimethyl-1,3-dioxen-4-one, and 10 mg of p-toluenesulfonic acid in 50 ml of toluene is heated at reflux under N2 for 4 hr. The solvent is removed under vacuum and the dark-colored residue is flash chromatographed on silica gel (1:1 hexane-EtOAc). The resulting product is recrystallized from EtOAc to give 11.0 g of 2-phthalimidoethyl acetoacetate.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([CH2:27][NH:28]C(=O)OC(C)(C)C)[CH2:23]2)=[N:4][CH:5]=[C:6]([C:8](=[O:21])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH:7]=1.[N:36]1[CH:41]=[C:40](B(O)O)[CH:39]=[N:38][CH:37]=1>>[NH2:28][CH2:27][C@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:40]3[CH:41]=[N:36][CH:37]=[N:38][CH:39]=3)=[CH:7][C:6]([C:8]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][C:17]([F:20])([F:18])[F:19])=[CH:14][CH:15]=3)=[O:21])=[CH:5][N:4]=2)[CH2:23]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Reactant: OB(O)c1cncnc1
Product: NC[C@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2cncnc2)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 93 using (R)-tert-butyl ((1-(3-bromo-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)carbamate (Stage 105.1) and pyrimidin-5-ylboronic acid. LC-MS (Condition 6) tR=0.86 min, m/z=459.0 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][S:30][CH2:31][C:32]([O:34]C)=[O:33])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][S:30][CH2:31][C:32]([OH:34])=[O:33])[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CSCCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CSCCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Yield: 99.9 %

Procedure:
A mixture of methyl [[6-(3,4,5-triphenyl-1H-pyrazol-1-yl)hexyl]thio]acetate (1.01 g, 2 mmol), 3N sodium hydroxide solution (2.1 mL, 6 mmol) and methanol (125 mL) was heated at reflux for 20 minutes. The solvent was removed and the residue treated with 1N hydrochloric acid solution. Extraction with dichloromethane (three times) followed by drying of the organic phase over sodium sulfate and concentration in vacuo afforded an oil that crystallized on standing to give [[6-(3,4,5-triphenyl-1H-pyrazol-1-yl) hexyl]thio]acetic acid (0.94 g, 96%); m.p.=92-97° C. MS(CI): m/e=471 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].[CH2:10]([O:12][C:13]([C:15]1[CH:19]=[CH:18][N:17]([CH:20]([CH3:22])[CH3:21])[C:16]=1[CH:23](Cl)[C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=1)=[O:14])[CH3:11].CCN(CC)CC>CCOC(C)=O>[CH2:10]([O:12][C:13]([C:15]1[CH:19]=[CH:18][N:17]([CH:20]([CH3:22])[CH3:21])[C:16]=1[CH:23]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([F:9])=[C:2]([Cl:1])[CH:3]=1)[C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=1)=[O:14])[CH3:11]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: CCOC(=O)c1ccn(C(C)C)c1C(Cl)c1ccc(C#N)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccn(C(C)C)c1C(Nc1ccc(F)c(Cl)c1)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Chloro-4-fluoroaniline (6.40 mmol) was added at 0° C. to a solution of 2-[chloro-(4-cyano-phenyl)-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid ethyl ester (Step H3) (3.20 mmol). Then Et3N (9.60 mmol) was added and the mixture was stirred at rt for 1 h. The mixture was diluted with EtOAc. The organic layer was washed successively with H2O (2×), brine, dried (Na2SO4), filtered and concentrated. The product was purified by flash chromatography to afford the title compound. tR: 5.96 min (HPLC 4); ESI-MS: tR=1.35 min, [M+H]+ 440/442 (LC-MS 1).
Reaction SMILES: FC(F)(F)S(O[C@H:7]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)[C:8]([F:11])([F:10])[F:9])(=O)=O.C([O-])([O-])=O.[K+].[K+].[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH2:38][NH2:39])[CH:33]=[CH:34][C:35]=1[O:36][CH3:37].O>C1CCCCC1>[Cl:19][C:14]1[CH:13]=[C:12]([CH:7]([NH:39][CH2:38][C:32]2[CH:33]=[CH:34][C:35]([O:36][CH3:37])=[C:30]([O:29][CH3:28])[CH:31]=2)[C:8]([F:11])([F:10])[F:9])[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: COc1ccc(CN)cc1OC
Reactant: O=S(=O)(O[C@H](c1ccc(Cl)c(Cl)c1)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCCCC1
Product: COc1ccc(CNC(c2ccc(Cl)c(Cl)c2)C(F)(F)F)cc1OC
Yield: 36.1 %

Procedure:
A solution of 144 (10.9 g, 28.9 mmol), K2CO3 (5.99 g, 43.4 mmol) and (3,4-dimethoxyphenyl)methanamine (6.77 g, 40.5 mmol) in cyclohexane (200 mL) and heated to 65° C. for 24 h. Water was added and the organic layer was concentrated and the crude product was purified by SiO2 chromatography eluting with EtOAc/hexane (5 to 20% EtOAc) to afford 4.11 g (36.1%) of 1-(3,4-dichlorophenyl)-N-(3,4-dimethoxybenzyl)-2,2,2-trifluoroethanamine (146).
Reaction SMILES: C([C:3]1[O:7][C:6]([C:8]([NH:10][C:11]2[S:12][C:13]([C:21]([CH:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:22])=[C:14]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[O:9])=[CH:5][CH:4]=1)=O.Cl.[NH2:30][OH:31]>C(O)C>[O:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[C:14]1[N:15]=[C:11]([NH:10][C:8]([CH:6]2[CH:5]=[CH:4][C:3](=[N:30][OH:31])[O:7]2)=[O:9])[S:12][C:13]=1[C:21]([CH:23]1[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1)=[O:22]
Reactant: O=Cc1ccc(C(=O)Nc2nc(-c3ccco3)c(C(=O)C3CCOCC3)s2)o1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: O=C(c1sc(NC(=O)C2C=CC(=NO)O2)nc1-c1ccco1)C1CCOCC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
Compound 513 (2.40 g, 6.00 mmol) was suspended in ethanol (24 mL), and hydroxylamine hydrochloride (438 mg, 6.30 mmol) was added thereto, followed by stirring at 60° C. for 1 hour. The precipitated solid was collected by filtration to afford the entitled Compound 514 (2.09 g, 84%) as a pale brown solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17](=[O:34])[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26]CC3C=CC=CC=3)=[CH:22][CH:21]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H-].[Na+].[C:37](OC)(=[O:42])[CH2:38][C:39]([CH3:41])=[O:40].C([Li])CCC>C1COCC1>[OH:40][C:39]1[CH2:41][C:17]([CH2:16][CH2:15][C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)([CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=2)[O:34][C:37](=[O:42])[CH:38]=1
Reactant: O=C(CCc1ccc(OCc2ccccc2)cc1)CCc1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1C=C(O)CC(CCc2ccc(O)cc2)(CCc2ccc(O)cc2)O1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The title compound was prepared as described in General Method 6 using 11.2 g (25 mmol) of 1,5-bis (4-benzyloxy-phenyl)-pentan-3-one (prepared in Example H), 1.0 g (25 mmol) of 60% NaH dispersion in mineral oil, 2.88 g (25 mmol) of methyl acetoacetate, 15.6 mL (1.6 M, 25 mmol) of n-butyllithium and 300 mL of THF. The reaction mixture was stirred for 12 hours at room temperature, quenched with aqueous NH4Cl, and worked up in the usual manner.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30]C(=O)OC(C)(C)C)[CH2:25]2)=[N:22][CH:23]=1.[Cl:38][C:39]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[C:41]([Cl:54])[C:40]=1[OH:55]>>[NH2:30][C@@H:26]1[CH2:27][CH2:28][CH2:29][N:24]([C:21]2[N:22]=[CH:23][C:18]([NH:17][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:43]5[CH:44]=[C:39]([Cl:38])[C:40]([OH:55])=[C:41]([Cl:54])[CH:42]=5)[CH:3]=4)[N:8]=[CH:7][C:6]=3[C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])=[CH:19][CH:20]=2)[CH2:25]1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Product: N[C@@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(Cl)c(O)c(Cl)c5)cc34)cn2)C1
Yield: 19.3 %

Procedure:
Following general procedure D, (R)-tert-butyl 1-(5-(6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino)pyridin-2-yl)piperidin-3-ylcarbamate (100 mg, 0.17 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (75 mg, 0.26 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (18 mg, 19% over 2 steps) as a yellow-orange solid. NMR (500 MHz, MeOD+TFA-d) δ 9.40 (br s, 1H), 8.25-8.19 (m, 2H), 8.10 (br s, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.65 (dd, J=9.1, 2.8 Hz, 1H), 7.32 (s, 2H), 7.07 (d, J=9.1 Hz, 1H), 4.53 (br s, 1H), 4.01 (dt, J=13.7, 4.0 Hz, 1H), 3.39-3.23 (m, 1H), 2.86 (br s, 1H), 2.22-2.12 (m, 1H), 1.97-1.88 (m, 1H), 1.78-1.64 (m, 2H), 1.26-1.16 (m, 4H). ESI MS m/z 548 [C29H27Cl2N5O2+H]+; HPLC>99.0% (AUC), tR=10.96 min.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:16]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClC(Cl)(Cl)Cl>[Br:16][C:1]1([C:7]2[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=[N+]([O-])c1ccc(C2CCCCC2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc(C2(Br)CCCCC2)cc1
Temperature: 80 °C
Reaction time: 4.5 h
Yield: 58.9 %

Procedure:
4-Cyclohexylnitrobenzene (22.6 g, 0.11 mol) and N-bromosuccinimide (21.6 g, 0.12 mol) were suspended in tetrachloromethane (200 mL) and a catalytic amount of dibenzoylperoxide was added. The reaction mixture was stirred at 80° C. for 4.5 hours. The reaction mixture was concentrated in vacuo and the residue dissolved in ethyl acetate (400 mL) and washed with water (100 mL). The aqueous phase was extracted with ethyl acetate (200 mL) and the combined organic phases were washed with water (3×150 mL), dried over MgSO4 and concentrated in vacuo. The residue was crystallised from ethyl acetate and heptane to give 18.4 g of 1-(bromocyclohexyl)-4-nitrobenzene.
Reaction SMILES: C([CH:8]([O:12][CH2:13][CH2:14][O:15]C1CCCCO1)[C:9]([O-:11])=[O:10])C1C=CC=CC=1.[CH3:22][C:23]1[CH:24]=[CH:25][C:26](S(O)(=O)=O)=[CH:27][CH:28]=1>CO>[OH:15][CH2:14][CH2:13][O:12][CH2:8][C:9]([O:11][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:10]
Reactant: O=C([O-])C(Cc1ccccc1)OCCOC1CCCCO1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: O=C(COCCO)OCc1ccccc1
Temperature: 25 °C

Procedure:
To a stirred solution of THP-protected hydroxy ester 3 (2 g, 6.8 mmol) in methanol (80 ml) was added p-TsOH (80 mg, 1 mg/ml). The reaction mixture was stirred at room temperature for 45 nm, concentrated and diluted with EtOAc. Organic layer was washed twice with NaHCO3 and water, dried over MgSO4, filtered and concentrated. The obtained residue was either used without further purification for next step or, if needed, purified by flash chromatography on silica gel (EtOAc/pentane 1/1) to give hydroxy ester 4 as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=S)[CH:10]([CH3:14])[CH2:9][NH:8][C:7]=2[N:15]=1.[C:16]([NH:19][NH2:20])(=O)[CH3:17]>C(O)CCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:16]([CH3:17])=[N:19][N:20]=[C:11]3[CH:10]([CH3:14])[CH2:9][NH:8][C:7]=2[N:15]=1
Reactant: COc1ccc2c(n1)NCC(C)C(=S)N2
Reactant: CC(=O)NN
Solvent: CCCCO
Product: COc1ccc2c(n1)NCC(C)c1nnc(C)n1-2
Temperature: 130 °C
Reaction time: 3 h
Yield: 60.7 %

Procedure:
To a solution of 7-methoxy-3-methyl-4,5-dihydro-1H-pyrido[2,3-b][1,4]diazepine-2(3H)-thione (1.8 g, 8.06 mmol) in n-butanol (25 mL) was added acetohydrazide (5.97 g, 80.61 mmol). The mixture was stirred at 130° C. for 3 hours. The reaction mixture was concentrated in vacuo and washed with brine (20 mL), and then the mixture was filtered through a celite pad. The filtrate was extracted with acetic ester (20 mL×3). The combined organic phase was dried by anhydrous sodium sulphate, and then filtered. The filtrate was concentrated and purified by column chromatograph silica gel (elute: dichloro methane/Methanol: 80:1→35:1→20:1) to give 8-methoxy-1,4-dimethyl-5,6-dihydro-4H-pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]diazepine (1.2 g, 61%) as a yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[C:13]2[CH2:14][CH2:15][CH2:16][C:12]=2[N:11]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[CH:19][CH:18]=2)[N:10]=1>CO.[OH-].[Na+].O>[C:24]([NH:23][C:20]1[CH:19]=[CH:18][C:17]([N:11]2[C:12]3[CH2:16][CH2:15][CH2:14][C:13]=3[C:9]([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:27])=[O:2])=[N:10]2)=[CH:22][CH:21]=1)(=[O:26])[CH3:25]
Reactant: COC(=O)CCCCCc1nn(-c2ccc(NC(C)=O)cc2)c2c1CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=O)Nc1ccc(-n2nc(CCCCCC(=O)O)c3c2CCC3)cc1
Yield: 64 %

Procedure:
A solution of the compound of Example 19 (0.13 g) in methanol (7 ml) and 1N sodium hydroxide (3.5 ml) was reacted at 25° C. for 2 hours. The solution was diluted with water, acidified, and the precipitate was extracted into ethyl acetate. The residue from drying and evaporation of solvent was recrystallized from acetonitrile to provide pure title compound (80 mg), m.p. 149°-150° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[F:12].O=S(Cl)Cl.[CH3:17]N(C=O)C>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:17])=[O:10])=[CH:4][C:3]=1[F:12]
Reactant: CN(C)C=O
Reactant: O=C(O)Cc1ccc(Br)c(F)c1
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)Cc1ccc(Br)c(F)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 801.5 %

Procedure:
To a mixture of 2-(4-bromo-3-fluorophenyl)acetic acid (5 g, 21.46 mmol) in MeOH (50 mL) was added SOCl2 (1.879 mL, 25.7 mmol) and DMF (0.166 mL, 2.146 mmol). Then the mixture was stirred at 80° C. for 16 h. The mixture was concentrated and extracted with EA (100 mL×2) and washed with NaHCO3 (100 mL) to give the organic layer. The combined organic extract was washed with brine, dried over Na2SO4, filtered, and concentrated to yield a brown oil of methyl 2-(4-bromo-3-fluorophenyl)acetate (5 g, 17.20 mmol, 80% yield): 1H NMR (400 MHz, MeOH-d4) δ 7.53 (t, J=7.6 Hz, 1H), 7.15 (dd, J=1.6, 9.6 Hz, 1H), 7.04-6.99 (m, 1H), 3.67 (s, 3H), 3.65 (s, 2H); ES-LCMS m/z 249.0 (M+H+2).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([OH:16])=[CH:11][C:10]=1[Cl:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([O:16][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:11][C:10]=1[Cl:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cc(O)cc(Cl)c1OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1cc(OC(=O)c2ccccc2)cc(Cl)c1OCc1ccccc1
Temperature: 0 °C
Yield: 90.6 %

Procedure:
To a solution of 27.3 g of 4-benzyloxy-3-chloro-5-methylphenol dissolved in 250 ml of chloroform and being stirred at 0° C. were added 15.4 g of benzoyl chloride and then 13.3 g of triethylamine. After stirring at room temperature for 2 hours, the chloroform layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel chromatography, which afforded 35 g of 4-benzyloxy-3-chloro-5-methyl-1-benzoyloxybenzene (90% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([O:22]C)[CH:19]=[C:18]([Cl:24])[C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([C@@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[CH3:16])[C:6]1=[O:17].B(Br)(Br)Br.O>C(Cl)Cl>[Cl:1][C:2]1[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([Cl:24])[C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([C@@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[CH3:16])[C:6]1=[O:17]
Reactant: COc1cc(Cl)c(CC2CCN([C@@H]3CCCC[C@@H]3C)C2=O)c(Cl)c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: C[C@H]1CCCC[C@H]1N1CCC(Cc2c(Cl)cc(O)cc2Cl)C1=O
Temperature: 0 °C
Yield: 85.7 %

Procedure:
Dissolve 3-(2,6-dichloro-4-methoxybenzyl)-1-(cis-2-methylcyclohexyl) pyrrolidin-2-one (1.29 g, 3.47 mmol) in DCM (100 mL) and cool to 0° C. Stir the solution under N2 and add BBr3 (2.61 g, 10.42 mmol). Continue to stir the reaction mixture for 2 hours and add water (100 mL). Extract the aqueous layer with dichloromethane (3×200 mL). Combine the organic layers and dry with Na2SO4, filter, concentrate and purify by flash column chromatography (silica gel, 40-100% of EtOAc-Hexane) to give 1.06 g (85%) of the title compound as a white solid: MS (APCI-pos mode) m/z (rel intensity) 356.1 (100), 358.1 (60).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:24]([C:25]2[CH:26]=[CH:27][C:28]([O:43][CH3:44])=[C:29]([CH:42]=2)[C:30]([NH:32][C:33]2([C:36]3[N:41]=[CH:40][CH:39]=[CH:38][N:37]=3)[CH2:35][CH2:34]2)=[O:31])=[CH:23][C:7]2[C:8]([C:18]3[NH:19][CH:20]=[CH:21][N:22]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=1)[CH3:2].[CH3:45][S:46](Cl)(=[O:48])=[O:47]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C.O>[CH2:1]([N:3]([C:4]1[C:24]([C:25]2[CH:26]=[CH:27][C:28]([O:43][CH3:44])=[C:29]([CH:42]=2)[C:30]([NH:32][C:33]2([C:36]3[N:41]=[CH:40][CH:39]=[CH:38][N:37]=3)[CH2:35][CH2:34]2)=[O:31])=[CH:23][C:7]2[C:8]([C:18]3[N:19]([S:46]([CH3:45])(=[O:48])=[O:47])[CH:20]=[CH:21][N:22]=3)=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[O:10][C:6]=2[CH:5]=1)[S:46]([CH3:45])(=[O:48])=[O:47])[CH3:2]
Reactant: CCNc1cc2oc(-c3ccc(F)cc3)c(-c3ncc[nH]3)c2cc1-c1ccc(OC)c(C(=O)NC2(c3ncccn3)CC2)c1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CCN(c1cc2oc(-c3ccc(F)cc3)c(-c3nccn3S(C)(=O)=O)c2cc1-c1ccc(OC)c(C(=O)NC2(c3ncccn3)CC2)c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(6-(ethylamino)-2-(4-fluorophenyl)-3-(1H-imidazol-2-yl)benzofuran-5-yl)-2-methoxy-N-(1-(pyrimidin-2-yl)cyclopropyl)benzamide (40 mg, 0.068 mmol) in pyridine (3.0 mL) at room temperature was added DMAP (16.60 mg, 0.136 mmol) followed by methanesulfonyl chloride (7.94 μl, 0.102 mmol). The reaction mixture was stirred at rt overnight, and then diluted with water. The mixture was extracted with EtOAc, and the organic extract washed with brine, dried over Na2SO4 and concentrated to obtain the title compound as an off white solid. Yield: 45 mg (89%). LCMS: (ES+) m/z=745.2 (M+H)+; Column—ACE Excel 2 C18 (50×3.0 mm-2 μm); M phase A: 2% MeCN-98% H2O-10 mM NH4COOH; M phase B: 98% MeCN-2% H2O-10 mM NH4COOH
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1>[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=1
Reactant: CC(C)(C)c1ccc(Br)cc1
Reactant: Cc1ccccc1B(O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1ccccc1-c1ccc(C(C)(C)C)cc1
Yield: 96.5 %

Procedure:
4-tert-butylbromobenzene (220 mg, 1.03 mmol) reacted with 2-methylphenylboronic acid (178 mg, 1.31 mmol) using 1 mol % of Pd(dba)2/Ph5FcP(t-Bu)2 and K3PO4 (424 mg, mmol) in toluene at 80° C. to give the title compound (223 mg, 97%) as a colorless oil: 1H-NMR (300 MHz, CDCl3): δ 7.49 (d, 2H, J=8.4 Hz), 7.34-7.30 (m, 6H), 2.36 (s, 3H), 1.44 (s, 9H). 13C{1H}-NMR (125 MHz, CDCl3): δ 149.50, 141.79, 138.88, 135.42, 130.26, 129.88, 128.81, 127.00, 125.69, 124.92, 34.51, 31.42, 20.58. GC/MS(EI): m/z (M+). Anal. Calcd for C17H20: C, 91.01; H, 8.99. Found: C, 90.72; H, 8.88.
Reaction SMILES: [Br:1][CH2:2][C:3](Cl)=[O:4].[CH2:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][NH:7]1.O>ClCCl>[Br:1][CH2:2][C:3]([N:7]1[CH2:8][CH2:9][C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6]1)=[O:4]
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=C(Cl)CBr
Solvent: ClCCl
Solvent: O
Product: O=C(CBr)N1CCc2ccccc2C1
Reaction time: 0.75 h

Procedure:
Bromoacetyl chloride (0.25 mL) was added slowly to a cold (5° C.) solution of 1,2,3,4-tetrahydroisoquinoline (0.8 g) in dichloromethane (25 mL) and the mixture was stirred in an ice bath for 45 minutes, then at room temperature overnight. Water (20 mL) was added, the layers were separated and the organic layer was washed in turn with 0.5N hydrochloric acid and sodium bicarbonate solution. The dried extract (MgSO4) was evaporated to provide 0.762 g of 2-(2-bromo-1-oxoethyl)-1,2,3,4-tetrahydroisoquinoline.