Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Br)(Br)[Br:2].N1C=CC=CC=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH2:21][CH2:22][CH2:23]O)[CH:15]=[C:16]([O:19][CH3:20])[C:17]=1[Cl:18]>C1(C)C=CC=CC=1>[Cl:18][C:17]1[C:12]([Cl:11])=[CH:13][C:14]([CH2:21][CH2:22][CH2:23][Br:2])=[CH:15][C:16]=1[O:19][CH3:20]
Reactant: BrP(Br)Br
Reactant: COc1cc(CCCO)cc(Cl)c1Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COc1cc(CCCBr)cc(Cl)c1Cl
Temperature: -5 °C
Reaction time: 0.25 h

Procedure:
In a four-necked flask fitted with a stirrer, internal thermometer, dropping funnel and calcium chloride tube is placed freshly distilled phosphorus tribromide (9.6 g., 0.036 mole) and dry toluene (50 ml.). To this is added dry pyridine (1.5 g.). The mixture is stirred for 15 minutes and then cooled to -5° C. A mixture of the product of Step 2 (23.5 g., 0.1 mole) and pyridine (0.5 g.) in toluene (50 ml.) is added dropwise with stirring at -5° C. to -3° C. over a one hour period. The reaction mixture is stirred at -5° C. to -3° C. for an additional hour and then allowed to warm up to 20°-25° C. The mixture is kept for 48 hours and then added to ice water (ca. 500 ml.). The toluene layer is separated and washed with water, dilute hydrochloric acid, sodium bicarbonate solution and again with water. After drying over Na2SO4 and evaporation of the toluene under reduced pressure there is obtained 2,3-dichloro-5-(3-bromopropyl)anisole.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[C:7]1([CH:13]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][OH:22])[CH2:16][CH2:15]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1(C)C=CC=CC=1>[C:4]([O:22][CH2:21][CH2:20][N:17]1[CH2:16][CH2:15][CH:14]([CH:13]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:19][CH2:18]1)(=[O:5])[CH2:3][C:2]([CH3:1])=[O:6]
Reactant: C=C1CC(=O)O1
Reactant: OCCN1CCC(C(c2ccccc2)c2ccccc2)CC1
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)OCCN1CCC(C(c2ccccc2)c2ccccc2)CC1
Temperature: 70 °C

Procedure:
Diketene (0.33 ml) was added to a solution of 4-diphenylmethyl-1-piperidineethanol (1.04 g) in toluene (2 ml) at 70° C. and the mixture was stirred at 70° C. for an hour. The solvent was distilled off under reduced pressure and the residue was purified by silica gel chromatography [hexane-ethyl acetate (2:3, v/v)] to give 2-(4-diphenylmethylpiperidino)ethyl acetoacetate as an oil. Yield 1.23 g (92.1%).
Reaction SMILES: [C:1]([O:7][CH2:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][C:16]([CH2:23][C@H:24]([N:26]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:27][CH2:28][O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][CH2:37][CH3:38])[CH3:25])=[CH:17][C:18]=2[C:20](=[O:22])[NH2:21])[CH2:13][CH2:12]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C([O-])=O.[NH4+]>CO.[Pd]>[C:1]([O:7][CH2:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][C:16]([CH2:23][C@H:24]([N:26]([C:39]([O:41][C:42]([CH3:43])([CH3:44])[CH3:45])=[O:40])[CH2:27][CH2:28][O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][CH2:37][CH3:38])[CH3:25])=[CH:17][C:18]=2[C:20](=[O:22])[NH2:21])[CH:13]=[CH:12]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CCOc1ccccc1OCCN(C(=O)OC(C)(C)C)[C@H](C)Cc1cc2c(c(C(N)=O)c1)N(CCCOC(=O)C(C)(C)C)CC2
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCOc1ccccc1OCCN(C(=O)OC(C)(C)C)[C@H](C)Cc1cc(C(N)=O)c2c(ccn2CCCOC(=O)C(C)(C)C)c1
Yield: 96.4 %

Procedure:
(R)-3-[5-[2-[N-(tert-Butoxycarbonyl)-N-[2- (2-ethoxy-phenoxy)ethyl]amino]propyl]-7-carbamoyl-2,3-dihydro-1H-indol-1-yl]propyl pivalate (8.53 g) was dissolved in methanol (280 ml), and 10% palladium on carbon (853 mg) and ammonium formate (3.97 g) were added to the solution. The mixture was heated under reflux for 13 hours, and the catalysts were filtered off. The solvent was removed in vacuo to give pale green amorphous (R)-3-[5-[2-[N-(tert-butoxycarbonyl)-N-[2-(2-ethoxyphenoxy)ethyl]amino]propyl]-7-carbamoyl-1H-indol-1-yl]propyl pivalate (8.20 g).
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.[Cl:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]3OC[CH2:20][NH:19][CH:18]([CH3:23])[C:16]3=2)[N:11]([S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH:10]=1.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C1COCC1>[Cl:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]3[O:5][CH2:3][CH2:2][N:19]([CH3:20])[CH:18]([CH3:23])[C:16]3=2)[N:11]([S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH:10]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC1NCCOc2ccc3c(c(Cl)cn3S(=O)(=O)c3ccccc3)c21
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC1c2c(ccc3c2c(Cl)cn3S(=O)(=O)c2ccccc2)OCCN1C
Reaction time: 0.5 h
Yield: 49.3 %

Procedure:
10-Chloro-1-methyl-8-(phenylsulfonyl)-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole trifluoroacetate (Example 98, 59 mg, 0.15 mmol) in MeOH (1 mL) was converted to the free amine by PL-HCO3 MP SPE (Polymer Laboratories) column. Formaldehyde (37 wt. % in H2O, 0.20 mL, 2.4 mmol) was added to a solution of the free amine (0.15 mmol) in THF (1 mL). After stirring for 10 minutes at room temperature sodium triacetoxyborohydride (26 mg, 0.12 mmol) was added and the mixture was stirred for an additional 30 minutes and evaporated. The crude material was purified by preparative HPLC (Xterra C18, 10 mM NH4HCO3 (pH 10) —CH3CN) to give the title compound as a white solid (28.9 mg). MS m/z 391 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:9]([NH:11][C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:21][CH2:22][CH2:23][C:24]1[C:28]2[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:27]=2[O:26][N:25]=1>CN(C=O)C>[Cl:1][C:2]1[C:10]2[C:9]([N:11]([CH2:21][CH2:22][CH2:23][C:24]3[C:28]4[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:27]=4[O:26][N:25]=3)[C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(CCCCl)noc2c1
Reactant: Clc1cccc2scc(Nc3ccncc3)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc2c(CCCN(c3ccncc3)c3csc4cccc(Cl)c34)noc2c1
Temperature: 70 °C
Yield: 36.3 %

Procedure:
A solution of 4-chloro-3-[(4-pyridinyl)amino]benzo[b]thiophene (2.26 g, 8.67 mmole) in 25 mL DMF was added to a suspension of NaH (0.416 g of 60% in oil, 10.4 mmole, washed with heptane). To this mixture was added 3-(3-chloropropyl)-6-fluorobenzisoxazole (2.04 g, 9.53 mmole) and the reaction mixture was heated at 70° C. for 3 hours. The reaction mixture was quenched into water and extracted with ethyl acetate (3×). The organics were washed with water and dried (MgSO4). The compound was purified via flash chromatography (EtOAc) to give 2.8 g of a partially solidified oil. This was recrystallized from methanol/water to give 1.38 g of a white powder, mp: 135°-136° C.
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[C:5]([C@H:7]2[CH2:12][CH2:11][N:10](C(OC)=O)[C@@H:9]([C:17]3[CH:22]=[C:21]([F:23])[C:20]([F:24])=[C:19]([F:25])[CH:18]=3)[CH2:8]2)[O:4][NH:3]1.C(O)(=O)C>Br>[F:25][C:19]1[CH:18]=[C:17]([C@H:9]2[CH2:8][C@@H:7]([C:5]3[O:4][NH:3][C:2](=[O:1])[CH:6]=3)[CH2:12][CH2:11][NH:10]2)[CH:22]=[C:21]([F:23])[C:20]=1[F:24]
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1cc(F)c(F)c(F)c1
Agent: Br
Solvent: CC(=O)O
Product: O=c1cc([C@H]2CCN[C@@H](c3cc(F)c(F)c(F)c3)C2)o[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.8 %

Procedure:
(2R,4S)-Methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(3,4,5-trifluorophenyl)piperidine-1-carboxylate (164 mg, 0.46 mmol) was dissolved in hydrogen bromide (33% in acetic acid (3.63 mL, 20.71 mmol) and the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2R,4S)-2-(3,4,5-trifluorophenyl)piperidin-4-yl)isoxazol-3(2H)-one (93 mg, 67%). 1H NMR (600 MHz, dmso) δ 1.29 (q, 1H), 1.43 (dq, 1H), 1.82-1.89 (m, 1H), 1.96-2.02 (m, 1H), 2.70 (dt, 1H), 2.79-2.87 (m, 1H), 3.05-3.12 (m, 1H), 3.64 (dd, 1H), 5.72 (s, 1H), 7.26-7.34 (m, 2H). HRMS Calculated for [C14H13F3N2O2+H]+: 299.1007. Found: 299.1002
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:34])=[C:5]([C:25]([O:32][CH3:33])=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH2:6][C:7]1[C:8](OS(C(F)(F)F)(=O)=O)=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11].C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Li+].B1([C:52]2[CH:57]=[CH:56][N:55]=[CH:54][CH:53]=2)OC(C)(C)C(C)(C)O1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:4]([CH3:34])=[C:5]([C:25]([O:32][CH3:33])=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH2:6][C:7]1[C:8]([C:52]2[CH:57]=[CH:56][N:55]=[CH:54][CH:53]=2)=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1cccc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)c1OS(=O)(=O)C(F)(F)F
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)c1-c1ccncc1
Temperature: 95 °C
Reaction time: 16 h
Yield: 90.9 %

Procedure:
To a solution of methyl 3-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-(trifluoromethanesulfonyl)oxybenzoate (385 mg, 0.7578 mmol) in toluene (8.6 ml) were added tetrakistriphenylphosphine palladium (26 mg, 0.0224 mmol), aqueous solution of sodium carbonate (2M aqueous solution, 0.99 ml), lithium chloride (64 mg, 1.5097 mmol) and ethanolic solution (1.59 ml) of pyridine-4-boronic acid pinacol cyclic ester (233 mg, 1.1365 mmol) and the mixture was heated with stirring at 95° C. for 16 hours. The reaction solution was diluted with ethyl acetate (100 ml), washed with water and dried and the solvent was evaporated therefrom. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the title compound (301 mg, 0.6887 mmol, 91%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH2:17][C@H:18]([N:20]([CH2:28][CH2:29][O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[O:37][CH2:38][C:39]([F:42])([F:41])[F:40])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:19])[CH:7]=[C:8]2[C:12]=1[N:11]([CH2:13][CH2:14][CH2:15][OH:16])[CH:10]=[CH:9]2)(=[O:3])[NH2:2].[CH2:43]([CH:45]([CH2:49][CH3:50])[C:46](Cl)=[O:47])[CH3:44].C(C(CC)C(O)=O)C.C(Cl)(=O)C(Cl)=O.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[CH2:43]([CH:45]([CH2:49][CH3:50])[C:46]([O:16][CH2:15][CH2:14][CH2:13][N:11]1[C:12]2[C:8](=[CH:7][C:6]([CH2:17][C@H:18]([N:20]([C:21]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:27])[CH2:28][CH2:29][O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:37][CH2:38][C:39]([F:40])([F:41])[F:42])[CH3:19])=[CH:5][C:4]=2[C:1](=[O:3])[NH2:2])[CH:9]=[CH:10]1)=[O:47])[CH3:44]
Reactant: CCC(CC)C(=O)Cl
Reactant: C[C@H](Cc1cc(C(N)=O)c2c(ccn2CCCO)c1)N(CCOc1ccccc1OCC(F)(F)F)C(=O)OC(C)(C)C
Agent: CCC(CC)C(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Solvent: c1ccncc1
Product: CCC(CC)C(=O)OCCCn1ccc2cc(C[C@@H](C)N(CCOc3ccccc3OCC(F)(F)F)C(=O)OC(C)(C)C)cc(C(N)=O)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.2 %

Procedure:
tert-Butyl (R)-N-[2-[7-carbamoyl-1-(3-hydroxy-propyl)-1H-indol-5-yl]-1-methylethyl]-N-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]carbamate (2.00 g) was dissolved in dry pyridine (3 ml), and 2-ethylbutyryl chloride (0.54 g) prepared from 2-ethylbutyric acid and oxalyl chloride was added to the solution. After the mixture was stirred overnight at room temperature, a saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium bicarbonate solution and brine subsequently, and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo, and the residue was purified by column chromatography on silica gel (eluent:hexane/ethyl acetate=2/1) to give white amorphous (R)-3-[5-[2-[N-(tert-butoxycarbonyl)-N-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]amino]propyl]-7-carbamoyl-1H-indol-1-yl]propyl 2-ethylbutyrate (1.66 g).
Reaction SMILES: [C:1]([O:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH:14]([CH2:17][N:18]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[S:19]([NH:22][C:23](=[O:38])[C:24]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=2)(=[O:21])=[O:20])[CH2:13][CH2:12]1)(=[O:8])C1C=CC=CC=1.[CH2:46]([N:53]=C=O)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C(Cl)(=O)C1C=CC=CC=1>>[CH2:46]([NH:53][C:1](=[O:8])[O:9][CH2:10][CH:11]1[CH2:12][CH2:13][CH:14]([CH2:17][N:18]([CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[S:19]([NH:22][C:23](=[O:38])[C:24]2[CH:25]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:27]=[C:28]([C:30]([F:32])([F:31])[F:33])[CH:29]=2)(=[O:21])=[O:20])[CH2:15][CH2:16]1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: O=C(NS(=O)(=O)N(Cc1ccccc1)CC1CCC(COC(=O)c2ccccc2)CC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C=NCc1ccccc1
Solvent: O=C(Cl)c1ccccc1
Product: O=C(NCc1ccccc1)OCC1CCC(CN(Cc2ccccc2)S(=O)(=O)NC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1

Procedure:
Following procedure to make (5), benzyl isocyanate was substituted for benzoyl chloride to give the title compound after purification. 1H NMR: (500 MHz, DMSO-d6): δ 12.43 (s, 1H), 8.45 (s, 2H), 8.31 (s, 1H), 7.58 (t, 1H), 7.35 (d, 2H), 7.27 (t, 4H), 7.19 (t, 3H), 4.48 (s, 2H), 4.13 (d, 2H), 3.68 (d, 2H), 3.30 (water), 3.12 (d, 2H), 2.48 (DMSO), 1.62 (m, 4H), 1.45 (m, 1H), 1.37 (m, 1H), 0.63 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][CH2:9][NH:10][C:11]([C:14]#[N:15])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].C[CH2:24][O:25]CC.CCN(C(C)C)C(C)C.ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O>C1COCC1.C(Cl)Cl>[C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][CH2:9][N:10]1[C:11]([CH3:13])([CH3:12])[CH2:14][NH:15][C:24]1=[O:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C#N)NCCNC(=O)OC(C)(C)C
Reactant: CCOCC
Agent: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: [Al+3]
Agent: [H-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCN1C(=O)NCC1(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 53 %

Procedure:
{2-[(Cyano-dimethyl-methyl)-amino]-ethyl}-carbamic acid tert-butyl ester (0.74 g., 3.3 mmol) was dissolved in THF (2 mL), cooled in an ice bath, and a 1.0 M solution of LiAlH4 in Et2O (6.5 mL, 6.5 mmol) was added dropwise. The resulting suspension was stirred in the ice bath for 3 h and then quenched (i. 0.17 mL of water; ii. 0.17 mL of 4 M aqueous NaOH; iii. 0.84 mL of water). The resulting mixture was diluted with THF (50 mL) and stirred for 15 min. The mixture was filtered and the filtrate concentrated to give an oil. The oil was dissolved in THF (10 mL), DIPEA (1.4 mL) was added, and the mixture was stirred in an ice bath. A solution of p-nitrophenyl chloroformate (800 mg, 4.0 mmol) in THF (8 mL) was added dropwise and the resulting yellow solution was stirred for 16 h. The mixture was concenatrated, dissolved in DCM (50 mL) and washed with 0.5 M HCl (50 mL) followed by saturated aqueous NaHCO3 solution (50 mL). The organic layer was dried (Na2SO4), concentrated and purified by flash chromatography (EtOAc) to give the product as a pale yellow gum (450 mg, 54%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH:10]1[CH:15]=[CH:14][C:13]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22]O)=[CH:12][CH:11]=1.N(C(N(C)C)=O)=NC(N(C)C)=O.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH2:16]([O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[C:13]1[CH:14]=[CH:15][CH:10]=[CH:11][CH:12]=1
Reactant: N#Cc1ccccc1O
Reactant: OCCOCCOCc1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: Cc1ccccc1
Product: N#Cc1ccccc1OCCOCCOCc1ccccc1
Reaction time: 2 h
Yield: 70.6 %

Procedure:
2-Hydroxybenzonitrile (300 mg, 2.52 mmol), di(ethylene glycol) benzyl ether (593 mg, 3.02 mmol), and 1,1′-azobis(N,N-dimethylformamide) (867 mg, 5.04 mmol) were dissolved in toluene (15 ml). Thereafter, tri-n-butylphosphine (1.26 ml, 5.04 mmol) was added at 20° C. to the obtained solution, and the obtained mixture was stirred at the same above temperature for 2 hours. The generated precipitate was filtrated, and the filtrate was then diluted with ethyl acetate (20 ml). The ethyl acetate solution was washed with water twice, and then with a saturated saline solution once. The resultant was dried over anhydrous sodium sulfate, and was then concentrated under reduced pressure. The obtained pale brown oil product was purified by silica gel column chromatography (dichloromethane), so as to obtain 2-[2-(2-benzyloxyethoxy)ethoxy]benzonitrile (529 mg, 71%) in the form of a colorless oil product.
Reaction SMILES: [CH2:1]([NH:5][C:6]([C:8]1[N:9]([CH2:27][CH2:28][CH2:29][C:30]#[N:31])[C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([O:17][CH2:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:26])=[CH:12][CH:11]=2)=[O:7])[CH:2]([CH3:4])[CH3:3].[N:32]([Si](C)(C)C)=[N+:33]=[N-:34].C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[CH2:1]([NH:5][C:6]([C:8]1[N:9]([CH2:27][CH2:28][CH2:29][C:30]2[NH:34][N:33]=[N:32][N:31]=2)[C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([O:17][CH2:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:26])=[CH:12][CH:11]=2)=[O:7])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CNC(=O)c1cc2cc(OCc3c(Cl)cccc3Cl)ccc2n1CCCC#N
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CC(C)CNC(=O)c1cc2cc(OCc3c(Cl)cccc3Cl)ccc2n1CCCc1nnn[nH]1
Yield: 37.5 %

Procedure:
To a solution of 1-(3-cyanopropyl)-5-(2,6-dichlorobenzyloxy)-1H-indole-2-carboxylic acid isobutyl amide (0.076 g, 0.17 mmol) in toluene (10 mL) was added azidotrimethylsilane (0.066 mL, 0.50 mmol) and dibutyltin oxide (0.012 g, 0.050 mmol). The reaction mixture was heated to reflux and stirred under argon at reflux temperature for 40 h. The solution was then cooled and the toluene removed under reduced pressure. Methanol was added and removed under reduced pressure. Ethyl acetate was added and the reaction mixture was washed with water and brine. The organic layer was dried over MgSO4, filtered, and the solvent removed under reduced pressure. Purification by flash chromatography (silica gel, 10% methanol/dichloromethane) yielded a white solid (0.032 g, 38%). MS(ES) m/e 501.2 [M +H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[C:19]([C:21]1[CH:30]=[CH:29][C:24]([C:25]([NH:27][NH2:28])=[O:26])=[CH:23][CH:22]=1)#[N:20]>>[Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([NH:28][NH:27][C:25](=[O:26])[C:24]2[CH:23]=[CH:22][C:21]([C:19]#[N:20])=[CH:30][CH:29]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(C(=O)NN)cc1
Reactant: Cc1c(N[C@@H](C(=O)O)[C@H](C)O)ccc(C#N)c1Cl
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(C#N)cc2)[C@H](C)O)ccc(C#N)c1Cl
Temperature: 0 °C
Yield: 78.4 %

Procedure:
(2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (intermediate 1a) (10.03 g, 37.3 mmol) and 4-cyano-benzohydrazide (6.02 g, 37.3 mmol) were coupled in an analogous procedure as described for the preparation of intermediate 3b. The crude product was purified by boiling in chloroform (100 mL) followed by cooling to 0° C. and filtration to yield product as a light yellow solid (12.05 g, 78%). 1H NMR (400 MHz, acetone-d6, δ in ppm) 9.81 (br s, 2H), 8.08 (AA′XX′, J=8.6 Hz, 2H), 7.91 (AA′XX′, J=8.7 Hz, 2H), 7.51 (d, J=8.7 Hz, 1H), 6.69 (d, J=8.8 Hz, 1H), 5.57 (d, J=7.0 Hz, 1H), 4.40 (m, 1H), 2.34 (dd, J=3.6, 6.9 Hz, 1H), 2.34 (s, 3H), 1.35 (d, J=6.4 Hz, 3H).
Reaction SMILES: P(Cl)(Cl)Cl.[Cl:5][C:6]1[CH:7]=[C:8]([C:13]2[N+:14]([O-])=[CH:15][CH:16]=[C:17]([Cl:19])[CH:18]=2)[N+:9]([O-])=[CH:10][CH:11]=1.[OH-].[Na+]>C(Cl)(Cl)Cl>[Cl:19][C:17]1[CH:16]=[CH:15][N:14]=[C:13]([C:8]2[CH:7]=[C:6]([Cl:5])[CH:11]=[CH:10][N:9]=2)[CH:18]=1
Reactant: [O-][n+]1ccc(Cl)cc1-c1cc(Cl)cc[n+]1[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClP(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Clc1ccnc(-c2cc(Cl)ccn2)c1
Temperature: 60 °C

Procedure:
2 mL of chloroform, 0.326 mL of phosphorus trichloride and 0.082 g of 4,4′-dichloro-2,2′-bipyridyl-N,N′-dioxide were added to a 100 mL round bottom flask equipped with a condenser, and the mixture was refluxed in a hot water bath for 75 hours. The reaction solution was cooled with ice, poured into crushed ice and neutralized with 25% NaOH to pH 7 or higher. Chloroform was removed from the solution by distilling off under reduced pressure. The precipitated white powder was collected by filtration and washed with water. The powder was dissolved in a small amount of petroleum ether and recrystallized in a refrigerator overnight to give white needle crystal. The crystal was dried by heating to 60° C. under reduced pressure to give 4,4′-dichloro-2,2′-bipyridine.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.[H-].[Na+].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][N:29]1[C:41]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:35]2[C:30]1=[CH:31][CH:32]=[CH:33][CH:34]=2>C1COCC1>[CH:40]1[C:41]2[N:29]([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:5]3([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][N:29]4[C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][C:35]=5[C:36]5[C:41]4=[CH:40][CH:39]=[CH:38][CH:37]=5)[C:4]4[CH:3]=[C:2]([Br:1])[CH:14]=[CH:13][C:12]=4[C:11]4[C:6]3=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=4)[C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:36]=2[CH:37]=[CH:38][CH:39]=1
Reactant: Brc1ccc2c(c1)Cc1cc(Br)ccc1-2
Reactant: BrCCCCCCCCCCn1c2ccccc2c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)C(CCCCCCCCCCn1c3ccccc3c3ccccc31)(CCCCCCCCCCn1c3ccccc3c3ccccc31)c1cc(Br)ccc1-2
Yield: 34.1 %

Procedure:
To a mixture of 5.2 g (16 mmol) 2,7-dibromofluorene in 300 mL THF was added 1.3 g (41 mmol) sodium hydride (75%) in several portions. A mixture of 15 g (39 mol) N-(10-bromodecyl)-carbazole (8) in 100 mL THF was added dropwisely at 70° C. and the mixture was refluxed for 48 h. After cooling, the solid was filtered and the filtrate was concentrated and dilute with water and extracted with CH2Cl2. The organic layer was collected and washed with brine and dried with anhydrous MgSO4. The crude product was further purified by silica column chromography to give 5.1 g (yield 34%, mp 94˜96° C.) title product. 1H NMR (CDCl3), δ (ppm): 8.10 (4H, d), 7.38˜7.48 (14 H, m), 7.23 (4H, t), 4.27 (4H, t), 0.88˜1.86 (36H, m). Anal. Calcd: C, 73.22; H, 6.68; N, 3.00. Found: C, 72.58; H, 6.59; N, 2.73.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].C(N(CC)CC)C.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccncc1F
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccncc1F)c1ccccc1
Reaction time: 2 h

Procedure:
A solution of 3-fluoropyridin-4-amine (2.20 kg, 19.6 mol) in anhydrous tetrahydrofuran (25 L) was cooled to −5° C. and flushed with nitrogen. This solution was charged with triethylamine (3.99 kg/5.5 L, 39.4 mol). Benzoylchloride (3.173 kg/2.62 l, 22.57 mol) was added drop-wise via an addition funnel over two hours while the internal temperature was maintained between −5° C. to 5° C. and the reaction mixture was left to stand for an additional two hours. The reaction mixture was then filtered and washed with dry tetrahydrofuran (5×20 L). The tetrahydrofuran solution was concentrated under vacuum to give crude product which was recrystallized from ethyl acetate and hexane, filtered and dried to afford N-(3-fluoro-pyridin-4-yl)-benzamide, 3.90 kg, (92%). 1H NMR (400 MHz, CDCl3): δ 8.51 (1H, t, J=5.46 Hz), 8.45 (1H, d, J=2.34 Hz), 8.39 (1H, d, J=5.46 Hz), 8.30 (1H, s), 7.89 (2H, d, J=8.20 Hz), 7.62 (1H, t, J=7.03 Hz), 7.53 (2H, t, J=7.81 Hz).