Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][CH2:9][C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15]([Cl:21])=[CH:16][CH:17]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[OH:30][CH2:31][CH2:32][CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[Cl:21][C:15]1[CH:14]=[C:13]2[C:18]([C:19](=[O:20])[C:10]([CH2:9][NH:8][C:6]([C:5]3[CH:28]=[CH:29][C:2]([N:36]4[CH2:37][CH2:38][CH:33]([CH2:32][CH2:31][OH:30])[CH2:34][CH2:35]4)=[N:3][CH:4]=3)=[O:7])=[CH:11][N:12]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:17][CH:16]=1
Reactant: OCCC1CCNCC1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(Cl)nc1
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(N2CCC(CCO)CC2)nc1

Procedure:
4-(2-Hydroxy-ethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate E and 4-(hydroxyethyl)piperidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.50 (d, J=2.01 Hz, 1H) 8.43 (t, J=5.65 Hz, 1H) 8.21 (d, J=9.04 Hz, 1H) 7.80-7.88 (m, 2H) 7.54-7.65 (m, 3H) 7.49-7.53 (m, 2H) 7.38 (dd, J=8.66, 1.88 Hz, 1H) 6.84 (d, J=2.00 Hz, 1H) 6.72 (d, J=8.78 Hz, 1H) 4.25-4.33 (m, 5H) 3.38 (q, J=6.10 Hz, 2H) 2.75 (t, J=12.50 Hz, 2H) 1.58-1.67 (m, 3H) 1.28 (q, J=6.53 Hz, 2H) 0.92-1.05 (m, 2H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:7]=1[C:8](Cl)=[O:9].[CH3:16][N:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22][C:23]#[N:24].Cl>ClCCCl>[Cl:5][C:6]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:7]=1[C:8]([C:21]1[N:17]([CH3:16])[C:18]([CH2:22][C:23]#[N:24])=[CH:19][CH:20]=1)=[O:9]
Reactant: Cn1cccc1CC#N
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cn1c(CC#N)ccc1C(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a suspension of 16.6 g. (0.125 mole) of aluminum chloride in 60 ml. 1,2-dichloroethane is added 26.2 g. (0.125 mole) of 2,4-dichlorobenzoyl chloride. The resulting solution is added slowly to a solution of 15 g. (0.125 mole) of 1-methylpyrrole- 2-acetonitrile in 60 ml. 1,2-dichloroethane while cooling externally with an ice bath. After the addition is complete, the mixture is stirred for 40 minutes at room temperature followed by heating at reflux for 3 minutes. It is then poured into ice acidified with dilute hydrochloric acid. The organic phase is separated and washed successively with N,N-dimethyl-1,3-propanediamine, 3N hydrochloric acid, and saturated sodium chloride solution. It is then dried over magnesium sulfate and the solvent evaporated. The resulting red oily residue is chromatographed on a column packed with neutral alumina and eluted with benzene and ether. The first compound-bearing fractions upon evaporation yield a white solid, 5-(2',4'-dichlorobenzoyl)-1-methylpyrrole- 2-acetonitrile, which is purified by recrystallization from methanol, m.p. 129°-130°C.
Reaction SMILES: ClC(OCC(C)C)=O.[C:9]([O:13][C:14]([NH:16][C@H:17]1[CH2:23][CH2:22][S:21][C@H:20]2[CH2:24][CH2:25][CH2:26][C@@H:27]([C:28]([OH:30])=O)[N:19]2[C:18]1=[O:31])=[O:15])([CH3:12])([CH3:11])[CH3:10].C[N:33]1CCOCC1.[NH4+].[OH-]>C(Cl)Cl>[C:28]([C@H:27]1[N:19]2[C@@H:20]([S:21][CH2:22][CH2:23][C@H:17]([NH:16][C:14](=[O:15])[O:13][C:9]([CH3:11])([CH3:10])[CH3:12])[C:18]2=[O:31])[CH2:24][CH2:25][CH2:26]1)(=[O:30])[NH2:33]
Reactant: CN1CCOCC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCS[C@H]2CCC[C@@H](C(=O)O)N2C1=O
Agent: CC(C)COC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CCS[C@H]2CCC[C@@H](C(N)=O)N2C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
Isobutyl chloroformate (31.2 mg, 0.229 mmol) was added to a solution of (4S,7S,10aS)-4-(tert-Butoxycarbonylamino)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylic acid (75 mg, 0.22 mmol) and 4-methylmorpholine (26.4 mg, 0.261 mmol) in DCM at 0° C. After stirring for 30 min at 0° C., NH4OH was added. The ice bath was removed and the reaction mixture was stirred at rt for 30 min. The reaction mixture was concentrated and the residue was partitioned between EtOAc and aqueous 0.5 N HCl. The organic phase was isolated, washed with saturated aqueous NaHCO3 and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated to give tert-butyl (4S,7S,10aS)-7-carbamoyl-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylcarbamate (67 mg, 0.20 mmol, 90% yield) as an oil. Anal. Calcd. for C15H25N3O4S m/z 343.4. found: 344.3 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:27])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S:23][CH:24]([CH3:26])[CH3:25])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.O1CCOCC1.CO.O>CC(O)C.C(Cl)Cl>[CH:24]([S:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:16]([NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:27])([CH3:26])[CH3:25]
Reactant: CCOC(=O)C1(NC(=O)c2ccccc2SC(C)C)Cc2ccccc2C1
Solvent: CC(C)O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)Sc1ccccc1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Reaction time: 480 h
Yield: 87.3 %

Procedure:
A 100 mL flask containing 2-(2-isopropylsulfanyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (326, 0.52 g, 1.45 mmol) is charged with 1,4-dioxane (8 mL) and MeOH (8 mL). A stirring bar is added and stirring is initiated. After dissolution, water (4 mL) is added followed by the LiOH monohydrate (145 mg, 3.46 mmol). After 20 days, tlc analysis (silica, 10% iPrOH/DCM) indicates that the starting material is completely consumed. The pH of the reaction mixture is carefully adjusted to pH 2 by slowly adding dilute aqueous HCl (3%, ˜9 mL). The contents of the flask are poured into a separatory funnel which contains EtOAc (40 mL). The layers are separated. The aqueous layer is extracted with EtOAc (20 mL). The combined organic phases are washed with water (20 mL) and brine (20 mL), and then dried over MgSO4, filtered and concentrated by pumping to constant weight to give off white solid (0.45 g, 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:14](=[O:15])[CH:13]=[CH:12][C:11]([C:16]([OH:18])=O)=[CH:10]1.[NH2:19][C:20]1[CH:21]=[C:22]([NH:27][C:28]([CH:30]2[CH2:32][CH2:31]2)=[O:29])[CH:23]=[CH:24][C:25]=1[CH3:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH:30]1([C:28]([NH:27][C:22]2[CH:23]=[CH:24][C:25]([CH3:26])=[C:20]([NH:19][C:16]([C:11]3[CH:12]=[CH:13][C:14](=[O:15])[N:9]([C:3]4[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[CH:10]=3)=[O:18])[CH:21]=2)=[O:29])[CH2:31][CH2:32]1
Reactant: Cc1ccc(NC(=O)C2CC2)cc1N
Reactant: O=C(O)c1ccc(=O)n(-c2c(Cl)cccc2Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(=O)C2CC2)cc1NC(=O)c1ccc(=O)n(-c2c(Cl)cccc2Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.9 %

Procedure:
To a solution of 1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid (30 mg) in DMF (0.6 mL) were added N-(3-amino-4-methylphenyl)cyclopropanecarboxamide (30 mg), HATU (60 mg) and iPr2NEt (62 mg) successively, and the mixture was stirred under a nitrogen atmosphere at room temperature for 16 hr. The reaction mixture was diluted with EtOAc (3 mL), and the resulting mixture was washed with 1 M HCl (3 mL×2), saturated aqueous NaHCO3 (3 mL×2) and brine successively, dried over MgSO4 and evaporated in vacuo. The residue was triturated with 10% MeOH in CH2Cl2, and the precipitates produced were collected by filtration to give N-{5-[(cyclopropylcarbonyl)amino]-2-methylphenyl}-1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide (25 mg).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][C@H:21]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=1)[CH2:22][C@H:23]1[O:28][C@@H:27]([CH2:29][C@@H:30]([O:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:26][C:25](=[O:42])[CH2:24]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Si:1]([O:18][CH2:19][CH2:20][C@H:21]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=1)[CH2:22][C@H:23]1[O:28][C@@H:27]([CH2:29][C@@H:30]([O:37][Si:38]([CH3:40])([CH3:39])[CH3:41])[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:26][C@@H:25]([OH:42])[CH2:24]1)([C:14]([CH3:16])([CH3:15])[CH3:17])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C[C@@H](C[C@H]1CC(=O)C[C@@H](C[C@H](CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)OCc2ccc(OC)cc2)O1)O[Si](C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)C[C@@H](C[C@H]1C[C@@H](O)C[C@@H](C[C@H](CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)OCc2ccc(OC)cc2)O1)O[Si](C)(C)C
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
To a solution of ketone 17 (59.0 mg, 0.0788 mmol, 1.0 equiv) in MeOH (5.0 mL, 0.015M) in a 15 mL rb flask at 0° C. was added NaBH4 (6.0 mg, 0.158 mmol, 2.0 equiv) in one portion. After 30 min at 0° C., the reaction was quenched by addition of acetone (0.1 mL), and then concentrated under reduced pressure. Purification was accomplished by flash chromatography column on a 3×12 cm column, eluting with 40% EtOAc/hexanes, collecting 18×150 mm test tube fractions. The product containing fractions (6-10) were combined and concentrated under reduced pressure to give the alcohol product 4 (55.6 mg, 94% yield) as colorless oil: Rf=0.40 (50% EtOAc/Hexanes); [α]D20=+16 (c=0.29, CHCl3); 500 MHz 1H NMR (CDCl3) δ 7.70-7.66 (m, 4H), 7.46-7.37 (m, 6H), 7.17 (d, J=8.7 Hz, 2H), 6.84 (d, J=8.7 Hz, 2H), 4.45 (d, J=10.8 Hz, 1H), 4.38 (d, J=11.1 Hz, 1H), 4.40-4.32 (m, 1H), 4.15-4.02 (dddddd, J=18.1, 10.7, 10.7, 7.1, 7.1, 7.1 Hz, 2H), 3.91-3.86 (m, 1H), 3.82-3.74 (m, 7H), 3.56-3.50 (m, 1H), 3.46-3.39 (m, 1H), 2.50 (d, J=5.5 Hz, 1H), 2.49 (d, J=3.0 Hz, 1H), 1.97 (ddd, J=12.4, 4.4, 2.4 Hz, 1H), 1.90-1.76 (m, 4H), 1.68-1.45 (m, 5H), 1.20 (t, J=7.1 Hz, 3H), 1.06 (s, 9H), 0.12 (s, 9H); 125 MHz 13C NMR (CDCl3) δ 171.8, 159.3, 135.8, 135.8, 134.1, 134.1, 131.2, 129.8, 129.5, 127.9, 127.9, 114.0, 72.9, 72.1, 72.1, 71.7, 68.3, 66.8, 60.7, 60.5, 55.5, 43.9, 42.9, 42.3, 41.8, 41.5, 37.8, 27.1, 19.4, 14.4, 0.5; 125 MHz DEPT 13C NMR (CDCl3) CH3 δ 55.5, 27.1, 14.4, 0.5; CH2 δ 71.7, 60.7, 60.5, 43.9, 42.9, 42.3, 41.8, 41.5, 37.8; CH δ 135.8, 135.8, 129.8, 129.5, 127.9, 127.9, 114.0, 72.9, 72.1, 68.4, 66.8; C δ 171.8, 159.3, 134.1, 134.1, 131.2, 19.4; IR (neat) 3440, 2940, 1735, 1612, 1513, 1428, 1376, 1250, 1175, 1109, 1037, 741, 704, 613, 536 cm−1; HRMS (ESI/APCI) calcd for C42H62O8Na (M+Na) 773.3881. found 773.3886.
Reaction SMILES: [Br:1][CH2:2][CH2:3][N:4]([CH2:21][CH3:22])[C:5]1[CH:10]=[CH:9][C:8](/[N:11]=[N:12]/[C:13]2[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1.Cl.[CH3:24][N:25]1[C:29]([CH3:30])=[CH:28][S:27]/[C:26]/1=[N:31]\[NH2:32].[OH-].[Na+]>C(O)(=O)C.O>[CH3:24][N:25]1[C:29]([CH3:30])=[CH:28][S:27]/[C:26]/1=[N:31]\[N:32]=[CH:17][C:16]1[CH:19]=[CH:20][C:13](/[N:12]=[N:11]/[C:8]2[CH:9]=[CH:10][C:5]([N:4]([CH2:3][CH2:2][Br:1])[CH2:21][CH3:22])=[CH:6][CH:7]=2)=[CH:14][CH:15]=1
Reactant: Cc1cs/c(=N\N)n1C
Reactant: CCN(CCBr)c1ccc(/N=N/c2ccc(C=O)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CCN(CCBr)c1ccc(/N=N/c2ccc(C=N/N=c3\scc(C)n3C)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 0.43 g of 4-((E)-{4-[(2-bromoethyl) (ethyl)amino]phenyl}diazenyl)benzaldehyde and 0.21 g of (2Z)-3,4-dimethyl-1,3-thiazol-2(3H)-one hydrazone hydrochloride in 10% acetic acid is stirred at room temperature for 60 minutes. Next, the preparation is diluted with 50 mL of water and cooled with ice. The reaction mixture is made neutral with 2N sodium hydroxide, then the precipitate that formed is suction filtered off, washed with water, and the product obtained is dried under vacuum.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:28][C:29]1[CH:30]=[CH:31][C:32]([CH3:38])=[C:33](B(O)O)[CH:34]=1>>[Cl:20][C:17]([F:19])([F:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:21]=[C:2]([C:31]3[CH:30]=[C:29]([F:28])[CH:34]=[CH:33][C:32]=3[CH3:38])[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=2)=[CH:11][CH:12]=1
Reactant: Cc1ccc(F)cc1B(O)O
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Product: Cc1ccc(F)cc1-c1cc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)cnc1N1CC[C@@H](O)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 290 using (R)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 171.1) and 5-Fluoro-2-methylphenylboronic acid to afford a white solid. HPLC (Condition 10) tR=6.424 min, UPLC-MS (Condition 11) m/z=492.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.60-1.92 (m, 2H) 1.94-2.11 (m, 3H) 2.78-3.03 (m, 1H) 3.07-3.28 (m, 3H) 4.11-4.23 (m, 1H) 4.76-4.94 (m, 1H) 7.10-7.19 (m, 1H) 7.23-7.31 (m, 1H) 7.33 (d, J=8.99 Hz, 3H) 7.86 (d, J=8.99 Hz, 2H) 7.91 (m, J=2.30 Hz, 1H) 8.73-8.79 (m, 1H) 10.08-10.17 (m, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:18]=3[F:24])=[N:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:25][CH3:26].C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[Br:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][C:10]2[C:9]3[C:14](=[CH:15][C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:1][S:35]([CH3:34])(=[O:37])=[O:36])=[C:7]([O:25][CH3:26])[CH:8]=3)[N:13]=[CH:12][N:11]=2)=[C:18]([F:24])[CH:19]=1
Reactant: COc1cc2c(Oc3ccc(Br)cc3F)ncnc2cc1OCCCN
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2c(Oc3ccc(Br)cc3F)ncnc2cc1OCCCNS(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.1 %

Procedure:
A solution of 7-(3-aminopropoxy)-4-(4-bromo-2-fluorophenoxy)-6-methoxyquinazoline (2.71 g, 6.4 mmol) and triethylamine (1.1 ml, 0.80 g, 7.9 mmol) in dichloromethane (15 ml) was treated with a solution of methanesulphonyl chloride (0.53 ml, 0.79 g, 6.9 mmol) in dichloromethane (10 ml) and stirred at ambient temperature, under nitrogen for 18 hours. The dichloromethane was then removed by evaporation and THF (4 ml) added. The resulting solution was treated with saturated aqueous sodium hydrogen carbonate solution (to pH 8), stirred vigorously for 30 minutes and the precipitate filtered, washed with water and dried to give 4-(4-bromo-2-fluorophenoxy)-6-methoxy-7-(3-(N-methylsulphonylamino)propoxy)quinazoline (2.98 g, 93%).
Reaction SMILES: [C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:6])[CH2:2][C:3]([O-])=[O:4].[H-].[Na+].[I:14][C:15]1[CH:27]=[CH:26][C:18]2[N:19](C)[C:20](=O)[O:21][C:22](=O)[C:17]=2[CH:16]=1>O1CCOCC1>[OH:21][C:22]1[C:17]2[C:18](=[CH:26][CH:27]=[C:15]([I:14])[CH:16]=2)[N:19]([CH3:20])[C:3](=[O:4])[C:2]=1[C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: CC(C)(C)OC(=O)CC(=O)[O-]
Reactant: Cn1c(=O)oc(=O)c2cc(I)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cn1c(=O)c(C(=O)OC(C)(C)C)c(O)c2cc(I)ccc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of tert-butyl malonate (5 ml, 20 mmol) in 1,4-Dioxane (70 ml) was added 60% Sodium hydride (0.8 g, 35 mmol) in portions. The mixture was stirred at room temperature for 45 min. then a solution of 6-iodo-1-methyl-1H-benzo[d][1,3]oxazine-2,4-dione (6.1 g, 20 mmol) in 1,4-Dioxane (40 ml) was added. The mixture was placed in an oil bath at 60° C. and the bath temp was raised to 120° C. over a period of 20 min after which stirring was continued for 90 min. The solvent was removed on a roto-evaporator and cold water (300 ml) was added to the residue. The mixture was washed with DCM (100 ml) then the aqueous phase was acidified with 2N HCl. The organic layer was extracted into DCM (2×100 ml) and after drying over MgSO4 the solvent was removed on a roto-evaporator. Yield=4.1 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:30]1[CH2:29][CH2:28][N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[Cl:20])[CH2:32][CH2:31]1)=[O:19])=[N:5]2
Reactant: Clc1ccccc1N1CCNCC1
Reactant: CCOC(=O)Nc1nc2cc(F)ccc2nc1OC
Product: COc1nc2ccc(F)cc2nc1NC(=O)N1CCN(c2ccccc2Cl)CC1
Yield: 87 %

Procedure:
Ethyl N-(6-fluoro-2-methoxyquinoxalin-3-yl)carbamate and 1-(2-chlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound (yield, 87%). 1H NMR (200 MHz, CDCl3): δ 3.14 (s, 4H), 3.79 (s, 3H), 4.13 (s, 4H), 6.97-7.05 (m, 2H), 7.22-7.28 (m, 2H), 7.33-7.40 (m, 2H), 7.46-7.51 (d, J=10.2 Hz, 1H), 7.66-7.73 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:24][CH3:25])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[S:17][C:10]=12.[C:26]1([CH2:32][C:33]([N:35]=[C:36]=[S:37])=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([N:24]([CH3:25])[C:36]([NH:35][C:33](=[O:34])[CH2:32][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[S:37])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[S:17][C:10]=12
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: CNc1ccc(Oc2ccnc3cc(-c4nccn4C)sc23)c(F)c1
Solvent: C1CCOC1
Product: CN(C(=S)NC(=O)Cc1ccccc1)c1ccc(Oc2ccnc3cc(-c4nccn4C)sc23)c(F)c1
Reaction time: 1 h
Yield: 19.6 %

Procedure:
To a suspension of the 222 (102 mg, 2.88 mmol) in THF (3 ml) was added 2-phenylacetyl isothiocyanate (51 mg, 0.288 mmol). The reaction mixture was stirred for 1 hr, transferred onto a chromatography column and eluted with a mixture EtOAc/MeOH (19:1) to afford title compound 223 (30 mg, 20% yield) as a white solid. 1HNMR: (DMSO-d6) δ (ppm): 10.88 (s, 1H), 8.51 (d, J=5.3 Hz, 1H), 7.91 (s, 1H), 7.41-7.18 (m, 6H), 7.04 (m, 4H), 6.5 (d, J=5.3 Hz, 1H), 4.0 (s, 3H), 3.6 (s, 2H), 3.43 (s, 3H). MS (m/z): 532.3 (M+1).
Reaction SMILES: C(O)(=O)C1C(=CC=CC=1)O.C(OO)(C)(C)C.C1(C)C=CC=CC=1.[C:24]1([S:30]([CH:33]([CH2:44][CH:45]=[C:46]([CH3:54])[CH2:47][CH2:48][CH:49]=[C:50]([CH3:53])[CH:51]=[O:52])[CH:34]=[C:35]([CH3:43])[CH2:36][CH2:37][CH:38]=[C:39]([CH3:42])[CH:40]=[O:41])(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[C:24]1([S:30]([CH:33]([CH2:44][CH:45]=[C:46]([CH3:54])[CH2:47][CH2:48][CH:49]=[C:50]([CH3:53])[CH2:51][OH:52])[CH:34]=[C:35]([CH3:43])[CH2:36][CH2:37][CH:38]=[C:39]([CH3:42])[CH2:40][OH:41])(=[O:32])=[O:31])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C=O)=CCCC(C)=CCC(C=C(C)CCC=C(C)C=O)S(=O)(=O)c1ccccc1
Agent: CC(C)(C)OO
Agent: O=C(O)c1ccccc1O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(=CCCC(C)=CCC(C=C(C)CCC=C(C)CO)S(=O)(=O)c1ccccc1)CO
Reaction time: 1.5 h
Yield: 44 %

Procedure:
To a stirred suspension of SeO2 (0.54 g, 4.82 mmol, 2 equiv) and salicylic acid (0.34 g, 2.41 mmol, 1 equiv) in CH2Cl2 (20 mL) at 0° C. was added a 3.0 M solution of t-butyl hydrogen peroxide (TBHP) in toluene (5.0 mL, 14.46 mmol, 6 equiv). The mixture was stirred at that temperature for 1.5 h, and a solution of the compound (J) (1.00 g, 2.41 mmol, 1 equiv) in CH.sub.2Cl.sub.2 (5 mL) was slowly added for 10 min. The reaction mixture was stirred at 0° C. for 3 h, diluted with CH2Cl2 (30 mL), washed with 10% NaOH solution (10 mL×3) and then saturated Na2S2O3 solution (10 mL×3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the diol compound (K) (0.47 g, 1.06 mmol) in 44% yield, together with the hydroxyl-aldehyde (0.13 g, 0.29 mmol, 12% yield), which was derived from further oxidation. Both of these two compounds can provide the dialdehyde of the Chemical Formula 3 after the Swern oxidation reaction.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][CH2:8]Cl)[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C(#N)C.CO.O>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][CH2:8][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:6]=1
Reactant: C1CCNCC1
Reactant: ClCCn1cc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Solvent: O
Product: Brc1cnn(CCN2CCCCC2)c1
Temperature: 60 °C

Procedure:
4-bromo-1-(2-chloroethyl)-1H-pyrazole (see Intermediate 29 for a preparation) (120 mg, 0.573 mmol), potassium carbonate (158 mg, 1.146 mmol) and Piperidine (0.113 mL, 1.146 mmol) was stirred in Acetonitrile (2 mL) and heated to 60° C. for five days. The mixture was fully dissolved in MeOH/water and loaded on to a 10 g SCX cartridge. The SCX cartridge was eluted with MeOH (100 ml), followed by 2M methanolic ammonia (50 ml). The basic fractions were evaporated to dryness to give the desired product (101 mg). LCMS (Method A): Rt=1.04, MH+=260
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH:34][C@@H:35]1[CH2:40][CH2:39][CH2:38][CH2:37][C@@H:36]1[OH:41])(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[C:26]([S:31]([NH:34][C@@H:35]4[CH2:40][CH2:39][CH2:38][CH2:37][C@@H:36]4[OH:41])(=[O:32])=[O:33])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:7][C:2]=2[F:1])=[CH:18][N:19]=1
Reactant: O=S(=O)(N[C@@H]1CCCC[C@@H]1O)c1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: Nc1ncc(-c2ccc(-c3ccccc3S(=O)(=O)N[C@@H]3CCCC[C@@H]3O)cc2F)cn1

Procedure:
The title compound was prepared using methods analogous to those described in Example 376 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine and racemic 2-bromo-N-((cis)-2-hydroxycyclohexyl)-benzene-sulfonamide. MS (ESI): mass calcd. for C22H23FN4O3S, 442.15; m/z found, 443.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.51 (d, J=1.3, 2H), 8.17 (dd, J=8.0, 1.4, 1H), 7.64-7.59 (m, 1H), 7.57-7.51 (m, 1H), 7.44-7.31 (m, 4H), 5.30 (s, 2H), 4.83 (d, J=7.7, 1H), 3.78 (s, 1H), 3.20-3.11 (m, 1H), 1.72-1.65 (m, 1H), 1.57-1.10 (m, 8H).
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].[CH3:13][C:14]([CH2:20][CH2:21][CH2:22][CH:23]([CH3:35])[CH2:24][CH2:25][CH2:26][CH:27]([CH3:34])[CH2:28][CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])=[CH:15][C:16](OC)=[O:17].O>S(=O)(=O)(O)O>[CH3:13][C:14]([CH2:20][CH2:21][CH2:22][CH:23]([CH3:35])[CH2:24][CH2:25][CH2:26][CH:27]([CH3:34])[CH2:28][CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])=[CH:15][C:16]([O:4][C:3]1[C:2]([O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]=1[OH:6])=[O:1])=[O:17]
Reactant: COC(=O)C=C(C)CCCC(C)CCCC(C)CCCC(C)C
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=CC(=O)OC1=C(O)[C@@H]([C@@H](O)CO)OC1=O)CCCC(C)CCCC(C)CCCC(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.55 g (3.1 mmol) of ascorbic acid was dissolved in concentrated sulfuric acid (14 mL). After addition of 1.0 g (3.1 mmol) of methyl 3,7,11,15-tetramethylhexadec-2-enoate, the mixture was stirred for 24 hours at room temperature. The reaction mixture was poured into iced water, and extracted with ethyl acetate. The extract was washed with water, 1M hydrochloric acid, saturated sodium bicarbonate aqueous solution, and saturated brine, successively, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (methanol/methylene chloride mixture) to obtain the title compound.