Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].CCN(CC)CC.C[N:13]1[C@@H:23]2[CH2:24][C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[C:27]4[O:32][C@H:17]5[C:18]([CH:20]=[CH:21][C@:22]2([OH:33])[C@:16]5([C:26]=34)[CH2:15][CH2:14]1)=[O:19]>CN1C(=O)CCC1.O.ClCCl>[CH2:3]=[CH:2][CH2:1][N:13]1[C@@H:23]2[CH2:24][C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[C:27]4[O:32][C@H:17]5[C:18]([CH2:20][CH2:21][C@:22]2([OH:33])[C@:16]5([C:26]=34)[CH2:15][CH2:14]1)=[O:19]
Reactant: C=CCBr
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)C=C[C@@]3(O)[C@H]1C5
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@@]3(O)[C@H]1C5
Temperature: 70 °C
Reaction time: 2 h
Yield: 84.3 %

Procedure:
Allyl bromide (56 mg; 0.463 mmol) and Et3N (45 μl; 0.327 mmol) were added to a suspension of noroxymorphone (Example 5, 100 mg; 0.348 mmol) in a mixture of NMP/H2O (10:1; 0.35 mL). The reaction vessel was purged with argon and the mixture was stirred at 70° C. for 2 h. At that time, additional Et3N (45 μl; 0.327 mmol) was added and the mixture was stirred for an additional 7.5 h at 70° C. The reaction mixture was then cooled to room temperature, diluted with dichloromethane (15 mL), and washed with saturated NaHCO3 (3×3 mL). The aqueous layer was re-extracted with dichloromethane (5 mL) and the combined organic layers were dried over MgSO4. Column chromatography of the residue (dichloromethane/methanol 4:1) afforded 96 mg (84%) of naloxone as a white solid mp: 181-182° C. (ethyl acetate), [lit. mp 173-175]xix [lit. 179.5° C. (toluene)]xx identical in all respects to the material described in the literature.xxi
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][NH:6]1)=[O:4].C(OC([C@@H]1C[C@H](S(C2C=CC=CC=2C(F)(F)F)(=O)=O)CN1)=O)C.Cl[C:47]1[N:52]=[CH:51][CH:50]=[CH:49][N:48]=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:20])[F:21])(=[O:11])=[O:12])[CH2:7][N:6]1[C:47]1[N:52]=[CH:51][CH:50]=[CH:49][N:48]=1)=[O:4]
Reactant: Clc1ncccn1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1
Agent: CCOC(=O)[C@@H]1C[C@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1ncccn1

Procedure:
In analogy to the procedure described in example 335a, (2S,4R)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester (prepared as described for the corresponding (2S,4S)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid ethyl ester in example 192e) was reacted with 2-chloro-pyrimidine (CAS Reg. No. 1722-12-9) in a shaking reactor at 150° C. for 48 h to give the title compound as yellow oil. MS (ESI): m/z=416.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1([C:12]([OH:14])=[O:13])[CH2:7][CH:6]([OH:8])[CH:5]2[CH:3]1[CH:4]2[C:9]([OH:11])=[O:10].[C-]#N.[K+].C([O-])(O)=O.[Na+].C(Br)C1C=CC=CC=1>CCO.O.CCOC(C)=O>[NH2:1][C:2]1([C:12]([OH:14])=[O:13])[CH2:7][C:6](=[O:8])[CH:5]2[CH:3]1[CH:4]2[C:9]([OH:11])=[O:10]
Reactant: NC1(C(=O)O)CC(O)C2C(C(=O)O)C21
Agent: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [C-]#N
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: NC1(C(=O)O)CC(=O)C2C(C(=O)O)C21
Temperature: 40 °C
Yield: 18.9 %

Procedure:
(1S*, 2S*, 4S*, 5R*, 6R*)-Ethyl 2-(3'-benzyl-5'-spirohydantoin)-4-hydroxybicyclo[3.1.0]hexane-6-carboxylate. To a stirred solution of the product of Example 1, step (c) (14.5 g, 78.7 mmol) in EtOH/H2O (2:1) (150 mL total volume) was added NH2CO2NH4 (18.42 g, 236 mmol) then KCN (7.68 g, 118 mmol). Upon complete addition, the reaction mixture was warmed at 40° C. for 2 days. The reaction mixture was concentrated in vacuo, partitioned with EtOAc/1N HCl, and brine. The mixture of hydantoins was extracted with EtOAc, dried over MgSO4, and concentrated. The crude hydantoins were reconstituted in DMF (50 mL) and stirred at room temperature as NaHCO3 (16.85 g, 200 mmol) and then benzyl bromide (12.6 g, 73.5 mmol) were consecutively added. The reaction mixture was warmed at 100° C. overnight. The reaction mixture was diluted with EtOAc and partitioned with 0.5N HCl. The hydantoins were extracted with EtOAC, washed with H2O then brine, dried over MgSO4, and purified via HPLC (hexanes/EtOAc) to afford 5.14 g (19%, 14.9 mmol) of the title compound. FDMS: M+ =344. Anal. calcd. for C18H20N2O5 : C, 62.78; H, 5.85; N, 8.13. Found: C, 62.97; H, 5.97; N, 8.06.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH:16]([C:17](OC)=[O:18])[O:15][NH:14][C:13]1=[O:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH3:23]>>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH:16]([C:17](=[O:18])[NH2:23])[O:15][NH:14][C:13]1=[O:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: COC(=O)C1ONC(=O)C1NC(=O)OCc1ccccc1
Solvent: O
Product: NC(=O)C1ONC(=O)C1NC(=O)OCc1ccccc1
Reaction time: 0.33 h

Procedure:
In 2.4 ml of concentrated ammonia water was dissolved 150 mg of 4-benzyloxycarbonylamino-5-methoxycarbonyl-3-isoxazolidinone (mixture of 4,5-cis compound and -trans compound). The solution was left standing at room temperature for 20 minutes, which was concentrated to dryness under reduced pressure. Ether was added to the concentrate to give 138 mg of 4-benzyloxycarbonylamino-5-carbamoyl-3-isoxazolidinone as crystals.
Reaction SMILES: [H][H].[C:3]([O:6][CH2:7][CH3:8])(=[O:5])[CH3:4]>>[C:3]([O:6][CH:7]([CH:7]([O:6][C:3](=[O:5])[CH3:4])[CH3:8])[CH3:8])(=[O:5])[CH3:4]
Reactant: CCOC(C)=O
Reactant: [H][H]
Product: CC(=O)OC(C)C(C)OC(C)=O
Yield: 37.9 %

Procedure:
A stream of hydrogen was used to transfer 5.3 mL (4.8 g) of ethyl acetate into the 16-lamp photoreactor. After irradiation for 20 h at 45° C., 1.8 g of the title product were obtained. The product was identified by comparison with the authentic compound made by hydrodimerizing vinyl acetate in the 4-lamp reactor at 25° C. to give 0.9 g of the product (52% yield) after the C--Hα to the --CO2 group.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[C:11]2[O:10][N:9]=[C:8]([NH2:12])[C:7]=2[CH:6]=[CH:5][CH:4]=1.[Cl:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:17]=1[C:18](Cl)=[O:19]>C1(C)C=CC=CC=1>[Cl:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:17]=1[C:18]([NH:12][C:8]1[C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:13])[F:14])[C:11]=2[O:10][N:9]=1)=[O:19]
Reactant: Nc1noc2c(C(F)(F)F)cccc12
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: Cc1ccccc1
Product: O=C(Nc1noc2c(C(F)(F)F)cccc12)c1c(Cl)cccc1Cl

Procedure:
7-(Trifluoromethyl)-3-aminobenzisoxazole (2 gram), 2,6-dichlorobenzoylchloride (2 gram), and 50 ml. of toluene are heated at reflux for 16 hours. After evaporation of the solvent at reduced pressure, the resultant oily semi-solid is triturated with ether. The solid so formed is then washed with ether and water and constitutes the desired product.
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][CH:4]=[C:3]([SH:7])[CH:2]=1.[C:9](#[N:12])[CH:10]=[CH2:11].C[O-].[Na+]>>[CH3:8][C:1]1[CH:2]=[C:3]([S:7][CH2:11][CH2:10][C:9]#[N:12])[CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cccc(S)c1
Reactant: C=CC#N
Agent: C[O-]
Agent: [Na+]
Product: Cc1cccc(SCCC#N)c1

Procedure:
β-(3-Methylphenyl)mercaptopropionitrile was prepared according to the procedure of Example 1 using m-toluenethiol (20.0 g; 0.16 moles), acrylonitrile (8.6 g; 0.16 moles) and sodium methoxide (0.5 g).
Reaction SMILES: C([O:4][CH2:5][C:6](=[O:35])[C@:7]1([O:30][CH2:31][O:32][CH2:33][CH3:34])[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([C@@H:22]([OH:26])[CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:27])[CH:17]=[CH:18]2)[C@@H:13]([CH3:28])[CH2:12]3)[CH2:9][C@@H:8]1[CH3:29])(=O)C.[OH-].[K+]>C(O)(=O)C>[CH2:33]([O:32][CH2:31][O:30][C@:7]1([C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([C@@H:22]([OH:26])[CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:27])[CH:17]=[CH:18]2)[C@@H:13]([CH3:28])[CH2:12]3)[CH2:9][C@@H:8]1[CH3:29])[C:6](=[O:35])[CH2:5][OH:4])[CH3:34]
Reactant: CCOCO[C@]1(C(=O)COC(C)=O)[C@@H](C)C[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCOCO[C@]1(C(=O)CO)[C@@H](C)C[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.5 %

Procedure:
A suspension of 0.7 g of 21-acetoxy-17α-ethoxymethoxy-11β-hydroxy-6α,16β-dimethyl-1,4-pregnadiene-3,20-dione in 8 ml of a 0.2N methanolic potassium hydroxide solution is stirred for 30 minutes at 0° C. and thereafter neutralized with 10% strength acetic acid. After performing the usual working-up steps, 470 mg of 17α-ethoxymethoxy-11β,21-dihydroxy-6α,16β-dimethyl-1,4-pregnadiene-3,20-dione is isolated, mp 100°-102° C.
Reaction SMILES: O[C:2]1[C:3](=[O:14])[NH:4][C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CN(C=O)C.C(Cl)(=O)C([Cl:23])=O>ClCCl>[Cl:23][C:2]1[C:3](=[O:14])[NH:4][C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C1NC(=O)C(c2ccccc2)=C1O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1NC(=O)C(c2ccccc2)=C1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
To a suspension of 3-hydroxy-4-phenyl-1H-pyrrole-2,5-dione (25.0 g, 0.13 mol) in dichloromethane (600 mL) under nitrogen was added DMF (36 mL). The suspension was cooled to ice temperature and treated with oxalyl chloride (40.0 g, 0.32 mol). The reaction mixture was subsequently refluxed overnight. After cooling to room temperature silica gel was added and the reaction mixture evaporated to dryness and subjected to flash chromatography (hexane:EtOAc 80:20). Trituration with dichloromethane, filtration and drying gave 17.6 g (64%) of the title compound. 1H NMR (400 MHz, CDCl3) δ 7.96-7.89 (m, 2H), 7.88-7.77 (bs, 1H), 7.55-7.45 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:30])[C:8]4[CH:20]=[C:19]([O:21][CH2:22][C@H:23]5[CH2:27][O:26][C:25]([CH3:29])([CH3:28])[O:24]5)[CH:18]=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:33]C(N(C)C)=O.CI>O>[Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:30])[C:8]4[CH:20]=[C:19]([O:21][CH2:22][C@H:23]5[CH2:27][O:26][C:25]([CH3:29])([CH3:28])[O:24]5)[CH:18]=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[N:12]2[CH3:33])=[CH:4][CH:3]=1
Reactant: CC1(C)OC[C@H](COc2ccc3c(c2)C(=O)c2c([nH]c4cc(Br)ccc24)C3(C)C)O1
Reactant: CC(=O)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: Cn1c2c(c3ccc(Br)cc31)C(=O)c1cc(OC[C@H]3COC(C)(C)O3)ccc1C2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To the mixture of 3-bromo-9-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl methoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound JJ3-1, 33.2 mg, 0.0706 mmol) and sodium hydride (60% in oil, 6.4 mg, 2.3 eq.), DMA (0.55 mL) and methyl iodide (0.015 mL, 3.4 eq.) were added under nitrogen atmosphere at 0° C., and the mixture was stirred at room temperature overnight. The reaction solution was added with water and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. After filtration and the concentration under reduced pressure, the resulting solid was washed with MTBE to obtain the title compound (white solid, 31.2 mg, 91%).
Reaction SMILES: CC(N=C=NC(C)C)C.[C:10]([NH:13][CH:14]([C:16]1[CH:17]=[CH:18][C:19]([Cl:44])=[C:20]([NH:22][C:23](=S)[NH:24][C:25]2[CH:26]=[C:27]([CH:38]=[CH:39][C:40]=2[NH:41][CH3:42])[C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([Br:37])=[CH:33][CH:32]=2)=[O:29])[CH:21]=1)[CH3:15])(=[O:12])[CH3:11]>CN(C=O)C>[C:10]([NH:13][CH:14]([C:16]1[CH:17]=[CH:18][C:19]([Cl:44])=[C:20]([NH:22][C:23]2[N:41]([CH3:42])[C:40]3[CH:39]=[CH:38][C:27]([C:28]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([Br:37])=[CH:33][CH:32]=4)=[O:29])=[CH:26][C:25]=3[N:24]=2)[CH:21]=1)[CH3:15])(=[O:12])[CH3:11]
Reactant: CNc1ccc(C(=O)Nc2ccc(Br)cc2)cc1NC(=S)Nc1cc(C(C)NC(C)=O)ccc1Cl
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: CC(=O)NC(C)c1ccc(Cl)c(Nc2nc3cc(C(=O)Nc4ccc(Br)cc4)ccc3n2C)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
N,N-Diisopropylcarbodiimide (46 L, 0.2 mmol) was added to 3-{3-[5-(1-acet-amidoethyl)-2-chlorophenyl]thioureido}-N-(4-bromophenyl)-4-(methylamino)benzamide (130 mg, 0.2 mmol) in DMF (2 mL) at rt. The mixture was stirred at 80° C. for 2 h, cooled and concentrated. The residue was purified by chromatography to give the title compound.
Reaction SMILES: [OH:1][C:2]1[C:6]([CH3:8])([CH3:7])[O:5][C:4](=[O:9])[CH:3]=1.C(N(CC)CC)C.[O:17](S(C(F)(F)F)(=O)=O)[S:18]([C:21]([F:24])([F:23])[F:22])(=O)=[O:19]>C(Cl)Cl>[F:22][C:21]([F:24])([F:23])[S:18]([O:1][C:2]1[C:6]([CH3:8])([CH3:7])[O:5][C:4](=[O:9])[CH:3]=1)(=[O:19])=[O:17]
Reactant: CC1(C)OC(=O)C=C1O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)OC(=O)C=C1OS(=O)(=O)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
To a −78° C. stirred solution of 4-hydroxy-5,5-dimethyl-5H-furan-2-one (250 mg, 1.95 mmol) in 18 mL of anhydrous CH2Cl2, was added triethylamine (0.40 mL, 2.9 mmol) and Tf2O (0.49 mL, 2.9 mmol). The reaction was stirred at −78° C. for 30 minutes, and quenched with saturated NH4Cl solution (10 mL). The mixture was warmed up to room temperature and separated. The aqueous layer was extracted with CH2Cl2 (2×20 mL). All organic layers were combined, dried over Na2SO4 and evaporated to brown oil, which was purified by plugging through a short pad of silica gel column with EtOAc/hexanes (1/3). Evaporation of solvents gave 2,2-dimethyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate as a light brown oil (450 mg, 89%).
Reaction SMILES: [N:1]1([CH2:5][C@H:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:9]=2)[NH2:7])[CH2:4][CH2:3][CH2:2]1.O[C:20]1[C:21]2[CH:29]=[N:28][CH:27]=[C:26]([C:30]([NH2:32])=[O:31])[C:22]=2[N:23]=[CH:24][N:25]=1>>[N:1]1([CH2:5][C@@H:6]([NH:7][C:20]2[C:21]3[CH:29]=[N:28][CH:27]=[C:26]([C:30]([NH2:32])=[O:31])[C:22]=3[N:23]=[CH:24][N:25]=2)[C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([C:15]([F:18])([F:16])[F:17])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: N[C@H](CN1CCC1)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: NC(=O)c1cncc2c(O)ncnc12
Product: NC(=O)c1cncc2c(N[C@H](CN3CCC3)c3ccc(Cl)c(C(F)(F)F)c3)ncnc12

Procedure:
Compound 20 was prepared following general synthetic scheme 7 wherein (S)-2-(azetidin-1-yl)-1-(4-chloro-3-(trifluoromethyl)phenyl)ethanamine was reacted with 4-hydroxypyrido[4,3-d]pyrimidine-8-carboxamide to give the title compound. LC-MS [451 (M+1)], 1H NMR (400 MHz, Chloroform-d) δ 10.43 (s, 1H), 9.75 (s, 1H), 9.59 (s, 1H), 8.62 (s, 1H), 7.98 (s, 1H), 7.69 (s, 1H), 7.48 (d, 2H), 6.12 (s, 1H), 5.18 (d, 1H), 3.25 (dq, 4H), 3.05-2.89 (m, 2H), 2.14 (p, 2H).
Reaction SMILES: C([O:3][C:4](=[O:27])[CH:5]([C:12]([NH:14][C:15]1[C:20]([CH:21]([CH3:23])[CH3:22])=[CH:19][CH:18]=[CH:17][C:16]=1[CH:24]([CH3:26])[CH3:25])=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)C.[OH-].[K+]>C(O)C>[CH3:23][CH:21]([C:20]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:24]([CH3:25])[CH3:26])[C:15]=1[NH:14][C:12]([CH:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:4]([OH:27])=[O:3])=[O:13])[CH3:22]
Reactant: CCOC(=O)C(C(=O)Nc1c(C(C)C)cccc1C(C)C)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)c1cccc(C(C)C)c1NC(=O)C(C(=O)O)c1ccccc1

Procedure:
In a manner similar to Example 134, α-[[[2,6-bis(1-methylethyl)phenyl]amino]carbonyl]-benzene acetic acid ethyl ester was saponified with KOH in ethanol to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:13][N:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1>>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:17]3[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH:16]=3)=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CN1CCC(=O)CC1
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Product: CN1CC=C(c2c[nH]c3cc([N+](=O)[O-])ccc23)CC1
Yield: 81.2 %

Procedure:
Beginning with 2.00 gm (12.3 mMol) 6-nitro-1H-indole and 3.00 mL (24.7 mMol) 1-methyl-4-piperidone, 2.57 gm (81%) of the title compound were recovered as a yellow solid.
Reaction SMILES: B([O-])([O-])O[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Br[C:18]1[CH:19]=[CH:20][C:21]2[N:27]([CH2:28][CH2:29][CH3:30])[CH2:26][CH2:25][C:24]([C:31]([NH:33][C:34]3[CH:39]=[CH:38][C:37]([CH2:40][N:41]([CH3:48])[CH:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)=[CH:36][CH:35]=3)=[O:32])=[CH:23][C:22]=2[CH:49]=1.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:48][N:41]([CH2:40][C:37]1[CH:36]=[CH:35][C:34]([NH:33][C:31]([C:24]2[CH2:25][CH2:26][N:27]([CH2:28][CH2:29][CH3:30])[C:21]3[CH:20]=[CH:19][C:18]([C:3]4[CH:8]=[CH:7][C:6]([N:9]5[CH2:14][CH2:13][O:12][CH2:11][CH2:10]5)=[CH:5][CH:4]=4)=[CH:49][C:22]=3[CH:23]=2)=[O:32])=[CH:39][CH:38]=1)[CH:42]1[CH2:43][CH2:44][O:45][CH2:46][CH2:47]1
Reactant: [O-]B([O-])Oc1ccc(N2CCOCC2)cc1
Reactant: CCCN1CCC(C(=O)Nc2ccc(CN(C)C3CCOCC3)cc2)=Cc2cc(Br)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCCN1CCC(C(=O)Nc2ccc(CN(C)C3CCOCC3)cc2)=Cc2cc(-c3ccc(N4CCOCC4)cc3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.9 %

Procedure:
4-morpholinophenyl borate (237 mg) and 7-bromo-1-propyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (391 mg) were dissolved in water:ethanol toluene (=1:1:10, v/v, 18.0 ml), and potassium carbonate (253 mg) was added thereto. This mixture was stirred at room temperature for 30 minutes under argon atmosphere, tetrakistriphenylphosphinepalladium (35 mg) was added thereto, and the mixture was heated to reflux for 10 hours under argon atmosphere. The reaction mixture was diluted with ethyl acetate, and washed with water and saturated brine. The organic layer was dried with anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate→ethyl acetate:ethanol=10:1), which was further recrystallized from ethyl acetate-diisopropyl ether-hexane to give N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-7-(4-morpholinophenyl)-1-propyl-2,3-dihydro-1-benzazepine-4-carboxamide (222 mg) as yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][S:11](=[O:15])(=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1C(=O)N([Br:23])C(=O)C1>C(Cl)Cl.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][S:11](=[O:15])(=[O:14])[CH2:12][CH2:13]2)=[CH:4][C:3]=1[Br:23]
Reactant: Nc1ccc(C2CCS(=O)(=O)CC2)cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Nc1ncc(C2CCS(=O)(=O)CC2)cc1Br
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 100 %

Procedure:
To an ice cold solution of 4-(6-aminopyridin-3-yl)tetrahydro-2H-thiopyran 1,1-dioxide (140 mg, 0.62 mmol) in DCM (15 mL) was added NBS (110 mg, 0.62 mmol) in two portions. The reaction mixture was stirred at 0° C. for 20 min. The reaction solution was diluted with ethyl acetate, washed with water, saturated aqueous sodium bicarbonate solution, brine, dried over sodium sulfate and concentrated to give 4-(6-amino-5-bromopyridin-3-yl)tetrahydro-2H-thiopyran 1,1-dioxide (190 mg, 0.62 mmol). LCMS (m/z): 305/307 (MH+), 0.33 min.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:13]=[C:12]([Cl:14])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.CO.[F:22][C:23]([F:34])([F:33])[O:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1.[BH3-]C#N.[Na+]>C(O)(=O)C>[Cl:14][C:12]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:5]([NH:4][CH2:3][CH2:2][NH:1][CH2:29][C:28]2[CH:31]=[CH:32][C:25]([O:24][C:23]([F:22])([F:33])[F:34])=[CH:26][CH:27]=2)[N:13]=1
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: FC(F)(F)Oc1ccc(CNCCNc2nc(Cl)nc3c2ncn3C2CCCC2)cc1
Reaction time: 0.5 h

Procedure:
281 mg of the product obtained in Stage 1 of Example 7, 4 ml of methanol, 0.16 ml of 4-trifluoromethoxy-benzaldehyde and 0.2 ml of acetic acid are mixed together, the reaction medium is agitated for 2 hours and 30 minutes, 0.1 g of NaBH3CN is added and agitation is carried out at ambient temperature for 1 hour. The solvent is evaporated off, the residue is chromatographed on silica eluting with CH2Cl2/methanol/ammonium hydroxide (95/0.5/0.33) and 129 mg of expected product is obtained.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Cl[CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=1.O>CN(C)C=O>[CH2:20]([O:19][C:17]([C:16]1[CH:22]=[CH:23][C:13]([O:12][CH2:11][CH2:10][CH2:9][N:3]2[CH:7]=[CH:6][N:5]=[CH:4]2)=[CH:14][CH:15]=1)=[O:18])[CH3:21]
Reactant: CCOC(=O)c1ccc(OCCCCl)cc1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCCCn2ccnc2)cc1
Temperature: 100 °C

Procedure:
Sodium hydride (0.6 g, 50% suspension in mineral oil) was added cautiously to a stirred and cooled solution of imidazole (0.79 g) in dry N,N-dimethylformamide (50 ml). After the initial vigorous reaction had subsided the mixture was heated to 100° C. for 10 minutes and then stirred at room temperature for a further 1 hour. Ethyl 4-(3-chloropropoxy)benzoate (2.8 g) was added over 2 minutes and the resulting mixture was heated on a steam bath for 6 hours and then cooled. Water (1 ml) was added to decompose any unreacted sodium hydride and the solution was evaporated and the residue was chromatographed on silica gel. Elution with chloroform gave mineral oil and small amounts of impurity. Elution with chloroform/methanol (20:1) gave the pure 1-[3-(4-ethoxycarbonylphenoxy)propyl]imidazole as an oil on evaporation of the solvent.
Reaction SMILES: C([Cl:4])(=O)C.[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])O)=[CH:8][CH:7]=1>ClCCl>[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[Cl:4])=[CH:8][CH:7]=1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)c1ccccc1F
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: Fc1ccc(C(Cl)(c2ccc(F)cc2)c2ccccc2F)cc1
Reaction time: 12 h

Procedure:
A 20% solution of acetyl chloride in dichloromethane (60 mL) was added to the crude bis(4-fluorophenyl)-2-fluorophenylmethanol at rt. The resulting solution was stirred for 12 h after which the solvent was removed by evaporation. Toluene (100 mL) was added to the residue and was then evaporated to afford crude bis(4-fluorophenyl)-2-fluorophenylchloromethane which was used without purification in the next step.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11](=[O:12])[O:10][N:9]=[C:8]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1.[Br:26]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:26][CH2:25][C:22]1[CH:21]=[CH:20][C:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:8]2[N:7]([CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[C:11](=[O:12])[O:10][N:9]=2)=[CH:24][CH:23]=1
Reactant: COCCOCn1c(-c2ccccc2-c2ccc(C)cc2)noc1=O
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COCCOCn1c(-c2ccccc2-c2ccc(CBr)cc2)noc1=O
Temperature: 80 °C
Reaction time: 6 h
Yield: 53.1 %

Procedure:
A mixture of 4-[(2-methoxyethoxy)methyl]-3-(4′-methylbiphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one (46.6 g), N-bromosuccinimide (26.9 g), α,α′-azobisisobutyronitrile (2.2 g) and carbon tetrachloride (500 mL) was stirred at 80° C. for 6 hr. Insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless oil (30.5 g, 53%).