Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]#[C:17][CH2:18][CH2:19]O)=[CH:13][CH:14]=2)[CH:9]=[N:8]1.C(N(CC)CC)C.[B-](F)(F)(F)[F:29].CCN([S+](F)F)CC.C([O-])(O)=O.[Na+]>ClCCl>[F:29][CH2:19][CH2:18][C:17]#[C:16][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[N:7]([CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[N:8]=[CH:9]2
Reactant: OCCC#Cc1ccc2c(cnn2C2CCCCO2)c1
Reactant: F[B-](F)(F)F
Agent: CCN(CC)[S+](F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: FCCC#Cc1ccc2c(cnn2C2CCCCO2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9.9 %

Procedure:
To a solution of 4-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-3-yn-1-ol (1.0 g, 3.7 mmol; Intermediate 20) in dry dichloromethane (25 mL), was added triethylamine.3HF (1.2 g, 7.4 mmol). XtalFluor-E (1.2 g, 5.5 mmol) was then added. The resulting solution was stirred at room temperature for 30 minutes. Upon completion, the reaction solution was neutralized by slow addition of saturated NaHCO3 (10 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0-20% EtOAc in petroleum ether) affording the title compound (100 mg). 1H NMR (400 MHz, DMSO-d6): δ 8.12 (s, 1H), 7.88 (s, 1H), 7.73 (d, 1H), 7.42 (dd, 1H), 5.86 (dd, 1H), 4.60 (dt, 2H), 3.88 (m, 1H), 3.78-3.71 (m, 1H), 2.89 (dt, 2H), 2.48-2.34 (m, 1H), 2.06-1.95 (m, 2H), 1.78-1.72 (m, 1H), 1.58 (m, 2H); LCMS: 273 (M+H)+.
Reaction SMILES: [CH2:1]([N:4]([CH2:27][CH2:28][CH3:29])[C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22]CC)=[O:21])=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)[CH2:2][CH3:3].[OH-].[Na+]>C(O)C>[CH2:27]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:25][CH:26]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:7]1)[CH2:28][CH3:29]
Reactant: CCCN(CCC)C1(c2ccc(C#Cc3ccc(C(=O)OCC)cc3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCN(CCC)C1(c2ccc(C#Cc3ccc(C(=O)O)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.1 %

Procedure:
Using General Procedure I; a solution of ethyl 4-[4-(1-dipropylamino-cyclopropyl)-phenylethynyl]-benzoate (Compound 109, 51.0 mg, 0.13 mmol) in ethanol (3 mL) and tetrahydrofluran (3 mL) was treated with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 32.0 mg (70%) of the title compound as a colorless solid.
Reaction SMILES: [CH3:1][C:2]([N:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[CH3:11])([CH3:5])[C:3]#[N:4].[C:12]1([Li])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])O.[Na+].[BH4-].[Na+]>C1COCC1.C(OCCCC)CCC.O>[CH3:5][C:2]([N:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[CH3:11])([CH3:1])[CH:3]([NH2:4])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: [Li]c1ccccc1
Reactant: CC1CCCN1C(C)(C)C#N
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCOCCCC
Solvent: O
Product: CC1CCCN1C(C)(C)C(N)c1ccccc1
Temperature: -70 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a solution of 2-methyl-2-(2-methyl-1-pyrrolidinyl)propanenitrile D25 (2.82 g; 18.56 mmol) in THF (100 ml) at −70° C. under argon was added over 15 minutes a solution of phenyllithium in dibutylether (20.6 ml of a 1.8M solution; 37.11 mmol). The reaction mixture was stirred at −70° C. for 2 hours then allowed to warm to room temperature and stirred overnight. Saturated aqueous sodium hydrogen carbonate (100 ml) was added and stirring continued for a further 10 minutes. The mixture was extracted with diethyl ether (2×150 ml). Combined organics were dried (Na2SO4) and evaporated in vacuo. The residual yellow oil was dissolved in methanol (100 ml) and sodium borohydride (2.12 g; 0.056 mol) added portionwise over 5 minutes. The reaction mixture was stirred at room temperature for 4 hours, further sodium borohydride (1 g; 0.026 mol) added and the mixture heated at 60° C. for 1.5 hours. The mixture was cooled and excess sodium borohydride decomposed by dropwise addition of water. The reaction mixture was evaporated in vacuo and the residue partitioned between saturated sodium hydrogen carbonate (150 ml) and DCM (150 ml). Solid potassium carbonate was added and the aqueous layer extracted with DCM (150 ml) Combined organic extracts were dried (Na2SO4) and evaporated to give a green oil. This was divided into 8 portions and each portion passed down a 10 g SCX column. After washing each column with DCM, 50% DCM in methanol and methanol the product was eluted with 1 M ammonia in methanol to yield the title compound as a pale yellow oil (3.46 g: 80%). Mass spectrum (Electrospray LC/MS), ES+: Found 233 (MH+). C15H24N2 requires 232. Ret. times 0.96 and 1.07 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:30][CH2:31][CH2:32][OH:33])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26](=[O:29])[NH:25][CH:24]=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.N1C=CN=C1.[C:39]([Si:43](Cl)([CH3:45])[CH3:44])([CH3:42])([CH3:41])[CH3:40]>C(Cl)Cl>[Si:43]([O:33][CH2:32][CH2:31][CH2:30][C@@:8]1([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26](=[O:29])[NH:25][CH:24]=3)=[CH:19][CH:18]=2)[CH3:16])[CH2:10][CH2:9]1)([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:45])[CH3:44]
Reactant: C[C@@H](c1ccc(-c2ccc(=O)[nH]c2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C[C@@H](c1ccc(-c2ccc(=O)[nH]c2)cc1)N1CC[C@](CCCO[Si](C)(C)C(C)(C)C)(c2ccc(F)cc2)OC1=O
Reaction time: 8 h
Yield: 27.2 %

Procedure:
A mixture of (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (100 mg, 0.78 mmol), imidazole (142.8 mg, 2.1 mmol), and tert-butylchlorodimethylsilane (350 mg, 2.34 mmol) in CH2Cl2 (20 mL) was stirred overnight. The mixture was washed with water and extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to give crude (R)-6-(3-(tert-butyldimethylsilyloxy)propyl)-6-(4-fluorophenyl)-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (120 mg), which was used for the next step without further purification.
Reaction SMILES: [CH2:1]([C:8]1[C:9]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:10]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:11]2[N:12]([CH:14]=[CH:15][CH:16]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:29]N1C(=O)CCC1=O>O1CCCC1>[CH2:1]([C:8]1[C:9]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:10]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:11]2[N:12]([C:14]([Cl:29])=[CH:15][CH:16]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1c(Cc2ccccc2)nn2cccc2c1-c1ccc(F)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1c(Cc2ccccc2)nn2c(Cl)ccc2c1-c1ccc(F)cc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 35.8 %

Procedure:
To a solution of ethyl 2-benzyl-4-(4-fluorophenyl)pyrrolo[1,2-b]pyridazine-3-carboxylate (730 mg) in tetrahydrofuran (10 ml) was added N-chlorosuccinimide (260 mg) and the mixture was stirred at 20° C. for 2 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with aqueous sodium thiosulfate, water and brine, dried over magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatograpy eluting with a mixture of toluene and ethyl acetate (10:1) to give ethyl 2-benzyl-7-chloro-4-(4-fluorophenyl)pyrrolo[1,2-b]pyridazine-3-carboxylate (285 mg) as an yellow oil.
Reaction SMILES: Cl.[OH:2][C@H:3]1[C@@H:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH2:8][C:7]2[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:6]=2[N:5]([CH2:23][CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])[C:4]1=[O:29].Cl.ClCCl.CO.[C:36](O)(=[O:38])[CH3:37]>C(OC(=O)C)(=O)C.CCOCC>[ClH:22].[C:36]([O:2][C@H:3]1[C@@H:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH2:8][C:7]2[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:6]=2[N:5]([CH2:23][CH2:24][CH2:25][N:26]([CH3:27])[CH3:28])[C:4]1=[O:29])(=[O:38])[CH3:37]
Reactant: COc1ccc([C@H]2Cc3cc(Cl)ccc3N(CCCN(C)C)C(=O)[C@H]2O)cc1
Reactant: CC(=O)O
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: CO
Solvent: ClCCl
Product: COc1ccc([C@H]2Cc3cc(Cl)ccc3N(CCCN(C)C)C(=O)[C@H]2OC(C)=O)cc1
Reaction time: 3 h

Procedure:
A stirred suspension of (cis)-3-(hydroxy)-7-chloro-1-[3-(dimethylamino)propyl]-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-2H-1-benzazepin-2-one, monohydrochloride (0.96 g; 2.18 mmol) in 35 ml of acetic anhydride was heated in an oil bath under argon and the resulting solution kept at 115°-118,° C. for 3 hours. The acetic anhydride was removed on a rotary evaporator at 0.2 mm to give a solid. The latter was rubbed under ethyl acetate, treated with 0.5 ml of saturated hydrogen chloride in ether to pH 2 and the evaporation repeated. The solid was rubbed under ether, evaporated, and pump-dried. The colorless material was rubbed under fresh ether, cooled overnight, filtered, washed with ether, and dried in vacuo; yield, 0.96 g; melting point 212°-215° C. (dec.), s, 200° C. TLC: Rf =0.32 (8:1:1, dichloromethane-methanol-acetic acid).
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[O:13][C:12]([CH2:14][N:15]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[N:16]3)=[CH:11][CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH3:3][C:4]1([C:9]2[O:13][C:12]([CH2:14][N:15]3[CH:19]=[CH:18][C:17]([NH2:20])=[N:16]3)=[CH:11][CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1
Reactant: CC1(c2ccc(Cn3ccc([N+](=O)[O-])n3)o2)OCCO1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Temperature: 75 °C
Reaction time: 0.67 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-3-nitro-1H-pyrazole (173 mg, 0.62 mmol), iron powder (105 mg, 1.86 mmol) and NH4Cl (167 mg, 3.10 mmol) in a mixture of EtOH (4.0 mL) and water (2.0 mL) was stirred at 75° C. for 40 min. The reaction mixture was filtered while hot and concentrated under reduced pressure. CH2Cl2 (15 mL) was added followed by water (15 mL). The aq. layer was extracted with CH2Cl2 (2×15 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 02: tR=0.62 min; [M+H]+=250.34.
Reaction SMILES: [N:1]1([CH:6]2[CH2:11][CH2:10][C:9](=O)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:13].[CH2:14]([O:21][C:22]1[CH:23]=[C:24]([NH:28]N)[CH:25]=[CH:26][CH:27]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[ClH:13].[ClH:13].[N:1]1([CH:6]2[CH2:11][C:10]3[C:25]4[C:24](=[CH:23][C:22]([O:21][CH2:14][C:15]5[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=5)=[CH:27][CH:26]=4)[NH:28][C:9]=3[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NNc1cccc(OCc2ccccc2)c1
Reactant: O=C1CCC(N2CCCC2)CC1
Agent: Cl
Solvent: CCO
Product: c1ccc(COc2ccc3c4c([nH]c3c2)CCC(N2CCCC2)C4)cc1

Procedure:
Following a procedure similar to that described in Example 2A and using 4-(1-pyrrolidyl)-cyclohexanone (14.5 g.), 3-benzyloxyphenylhydrazine hydrochloride (21.8 g.), 160 ml. of absolute ethyl alcohol and 60 ml. of 4.5N ethanolic hydrogen chloride there was obtained 3-(1-pyrrolidinyl)-7-benzyloxy-1,2,3,4-tetrahydrocarbazole hydrochloride, 4 g. of which was hydrogenated, following a procedure similar to that described in Example 1C to give 1.3 g. of 3-(1-pyrrolidyl)-7-hydroxy-1,2,3,4-tetrahydrocarbazole hydrochloride, m.p. 294°-295° C. (methyl alcohol-water).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([S:12]([N:15]=[CH:16][N:17]([CH3:19])[CH3:18])(=[O:14])=[O:13])[CH:6]=1)([CH3:4])[CH3:3].[Cl:20][CH2:21][C:22]([NH:24][CH2:25]O)=[O:23]>S(=O)(=O)(O)O>[Cl:20][CH2:21][C:22]([NH:24][CH2:25][C:9]1[CH:10]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[CH:6]=[C:7]([S:12]([N:15]=[CH:16][N:17]([CH3:19])[CH3:18])(=[O:13])=[O:14])[C:8]=1[OH:11])=[O:23]
Reactant: O=C(CCl)NCO
Reactant: CN(C)C=NS(=O)(=O)c1cc(C(C)(C)C)ccc1O
Agent: O=S(=O)(O)O
Product: CN(C)C=NS(=O)(=O)c1cc(C(C)(C)C)cc(CNC(=O)CCl)c1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3 g (0.01 mole) of 4-(1,1-dimethylethyl)-2-dimethylaminomethyleneaminosulfonylphenol are dissolved in 30 ml of sulfuric acid, and 1.1 g (0.009 mole) of 2-chloro-N-hydroxymethylacetamide are added. The mixture is stirred for 30 minutes at room temperature and poured into ice water. The product is filtered off with suction and recrystallized from methanol.
Reaction SMILES: COC(=O)C[C:5](=[O:34])[N:6]([CH2:9][C:10]1[CH:15]=[C:14]([C:16](=[O:22])[NH:17][O:18][CH2:19][CH2:20][OH:21])[C:13]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:25]=2[F:31])=[C:12]([F:32])[C:11]=1[F:33])[O:7][CH3:8].[CH3:36][O-:37].[Na+]>CO.[Cl-].[NH4+]>[F:32][C:12]1[C:13]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:25]=2[F:31])=[C:14]([CH:15]=[C:10]([CH2:9][N:6]([C:5](=[O:34])[CH2:36][OH:37])[O:7][CH3:8])[C:11]=1[F:33])[C:16]([NH:17][O:18][CH2:19][CH2:20][OH:21])=[O:22]
Reactant: COC(=O)CC(=O)N(Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F)OC
Reactant: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CON(Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F)C(=O)CO
Reaction time: 2 h
Yield: 44.5 %

Procedure:
To a solution of acetoxyacetic acid (13.9 mg, 0.12 mmol) in methylene chloride (1 ml) were added 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (18.9 mg, 0.12 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (22.5 mg, 0.12 mmol), and the mixture was stirred for 3 hours. This solution was added dropwise to a solution of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(methoxyamino-methyl)-benzamide (50.0 mg, 0.10 mmol) obtained in Example 15 in THF (2 ml), and triethylamine (40.9 μl, 0.29 mmol) was added thereto. The mixture was stirred for 24 hours. The reaction mixture was diluted with ethyl acetate (45 ml), and washed with saturated aqueous ammonium chloride (20 ml), and then with saturated brine (2×20 ml). The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resultant residue was roughly purified by preparative TLC (CH2Cl2/MeOH (10:1)) to give {[2,3-difluoro-4-(2-fluoro-4-iodo-phenylamino)-5-(2-hydroxy-ethoxycarbamoyl)-benzyl]-methoxy-carbamoyl}acetic acid methyl ester (14.0 mg, containing impurities) as a colorless oil. To a solution of the resultant {[2,3-difluoro-4-(2-fluoro-4-iodo-phenylamino)-5-(2-hydroxy-ethoxycarbamoyl)-benzyl]-methoxy-carbamoyl}acetic acid methyl ester (14.0 mg, containing impurities) in methanol (1 ml) was added sodium methoxide (3.0 mg, 0.06 mmol), and the mixture was stirred for 2 hours. The reaction mixture was diluted with saturated ammonium chloride, and extracted with methylene chloride (30 ml and 15 ml). The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resultant residue was purified by preparative TLC (CH2Cl2/MeOH (10:1)) to give 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-{[(2-hydroxy-acetyl)-methoxy-amino]-methyl}-N-(2-hydroxy-ethoxy)-benzamide (F-5, 5.8 mg, 12% for 2 steps) as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH2:18][OH:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:30]>CN(C)C=O>[CH2:20]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH2:18][O:19][CH3:30])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CI
Reactant: O=[N+]([O-])c1cccc(N(Cc2ccccc2)Cc2ccccc2)c1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1c(N(Cc2ccccc2)Cc2ccccc2)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
The product from Example 46B (0.12 g, 0.33 mmoles) in anhydrous N,N-dimethylformamide (1 mL) was treated with 60% sodium hydride (0.016 g, 0.40 mmoles). After stirring for 10 minutes at room temperature, the mixture was treated with iodomethane (0.031 mL, 0.50 mmoles) and allowed to stir overnight at room temperature. The reaction mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate (3×). The ethyl acetate phases were combined, dried with sodium sulfate, filtered and the filtrate concentrated under reduced pressure to provide the title compound. MS (ESI+) m/z 363 (M+H)+.
Reaction SMILES: [CH3:1][CH2:2][C:3](=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[BH4-].[Na+]>CO>[CH3:1][CH2:2][CH:3]([OH:10])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCC(=O)CC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCC(O)CC
Reaction time: 8 h
Yield: 96.3 %

Procedure:
20.5 g (144 mmol) of 3-nonanone are initially charged in 200 ml of methanol, 5.45 g (144 mmol) of sodium borohydride are added a little at a time at room temperature and the mixture is stirred overnight. The solvent is removed under reduced pressure and the mixture is then acidified and extracted with dichloromethane. The organic phase is dried over sodium sulphate. Removal of the solvent gives 20 g (96%) of a colourless oil.
Reaction SMILES: [N:1]1([C:11]2[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[CH:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.O>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:8]1[CH:7]=[CH:6][C:5]2[CH2:4][CH2:3][CH2:2][N:1]3[C:10]=2[C:9]=1[C:12]1[C:13](=[O:17])[CH2:14][CH2:15][CH2:16][C:11]=13
Reactant: O=C1C=C(N2CCCc3ccccc32)CCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCCc2c1c1cccc3c1n2CCC3
Yield: 98.9 %

Procedure:
Cupric acetate (878 mg) was added to a solution of 3-(1,2,3,4-tetrahydro-1-quinolinyl)-2-cyclohexen-1-one (500 mg) and palladium (II) acetate (100 mg) in dry DMF (10 ml). The mixture was heated at 135° under nitrogen for 3 h, cooled, poured into water (100 ml) and extracted with ethyl acetate (4×50 ml). The combined, dried organic extracts were evaporated to give a solid (ca. 490 mg) which was purified by FCC eluting with ethyl acetate:hexane (2:1) to give the title compound (285 mg), m.p. 160°-164°.
Reaction SMILES: [CH:1]1([S:6][C:7]2[C:12]([CH2:13]O)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O=S(Cl)[Cl:17]>CC#N>[Cl:17][CH2:13][C:12]1[C:7]([S:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: OCc1cccnc1SC1CCCC1
Reactant: O=S(Cl)Cl
Solvent: CC#N
Product: ClCc1cccnc1SC1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(2-Cyclopentylsulfanyl-pyridin-3-yl)-methanol (0.6 g, 2.87 mmol) obtained in Step B was dissolved in CH3CN (5 mL), and SOCl2(0.42 mL, 5.74 mmol) was added thereto at 0° C. The mixture was stirred at room temperature for 2 hours. After the termination of the reaction, the reactant was concentrated under reduced pressure to obtain the title compound, which was used in the next step without a separate purification process.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[C:12]([C:16]3[CH:21]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:19]=[C:18]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:17]=3)[C:13]=1[O:14][CH3:15])[CH2:10][C:9]([CH3:30])=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1.[Li]CCCC.[Cl:43][Si:44](Cl)([CH3:46])[CH3:45]>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]2[C:11]([CH:10]=[C:9]([CH3:30])[CH:8]2[Si:44]([Cl:43])([CH3:46])[CH3:45])=[C:12]([C:16]2[CH:21]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:19]=[C:18]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:17]=2)[C:13]=1[O:14][CH3:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1c(C(C)(C)C)cc2c(c1-c1cc(C(C)(C)C)cc(C(C)(C)C)c1)CC(C)=C2
Reactant: C[Si](C)(Cl)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1c(C(C)(C)C)cc2c(c1-c1cc(C(C)(C)C)cc(C(C)(C)C)c1)C=C(C)C2[Si](C)(C)Cl
Temperature: -20 °C
Reaction time: 10 h
Yield: 99.5 %

Procedure:
To a solution of 15.7 g (38.8 mmol) of 5-tert-butyl-7-(3,5-di-tert-butylphenyl)-6-methoxy-2-methyl-1H-indene in 200 ml of toluene 16.0 ml (40.0 mmol) of 2.5 M nBuLi in hexanes was added at room temperature. The resulting viscous solution was stirred for 10 h, and then 10 ml of THF was added. This mixture was stirred for 2 h at 60° C., then cooled to −20° C., and 25.0 g (194 mmol, 5 eq.) of dichlorodimethylsilane was added in one portion. The resulting solution was refluxed for 2 h, then evaporated to ca. ¾ of its volume, and filtered through glass frit (G3). The precipitate was additionally washed by 2×30 ml of toluene. The combined filtrate was evaporated to dryness to give 19.2 g (99%) of white solid which was further used without an additional purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C1(C)C=CC(S(O[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][Cl:30])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:3][C:2]([O:1][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][Cl:30])=[CH:7][CH:6]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCCCCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClCCCCCCOc1ccc(-c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
A mixture of 4-hydroxybiphenyl (34 g), 1-(p-toluenesulfonyloxy)-6-chlorohexane (60 g), anhydrous potassium carbonate (60 g) and dimethylformamide (400 ml) was stirred at 60° C. for 6 hours. Excess potassium carbonate was removed by filtration. Water and ethyl acetate were then added and the resultant solution washed with water, dried with magnesium sulfate and evaporated. The resulting crude residue was then dissolved in ethyl acetate/hexane and recrystallized to yield 1-(4-biphenyloxy)-6-chlorohexane.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[C:6]([C:10]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)[C:13](=[O:25])[O:12][N:11]=2)=[N:7][O:8][N:9]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:26][S:27]([O:1][CH2:2][CH2:3][NH:4][C:5]1[C:6]([C:10]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:24])[F:23])[CH:16]=3)[C:13](=[O:25])[O:12][N:11]=2)=[N:7][O:8][N:9]=1)(=[O:29])=[O:28]
Reactant: O=c1onc(-c2nonc2NCCO)n1-c1cccc(C(F)(F)F)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCNc1nonc1-c1noc(=O)n1-c1cccc(C(F)(F)F)c1
Reaction time: 0.08 h
Yield: 95.1 %

Procedure:
To a solution of 3-{4-[(2-hydroxyethyl)amino]-1,2,5-oxadiazol-3-yl}-4-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5(4H)-one (1.0 g, 2.9 mmol) in ethyl acetate (8.5 mL) was added methanesulfonyl chloride (0.29 mL, 3.7 mmol) in one portion. The reaction was stirred for 5 minutes and triethylamine (0.52 mL, 3.7 mmol) was added, also in one portion. After stirring for an additional 10 minutes, the reaction was quenched with the addition of water (5 mL). The product was extracted with ethyl acetate (2×5 mL), dried over sodium sulfate and concentrated in vacuo to give the desired product (1.2 g, 99%). LCMS calculated for C14H13F3N5O6S (M+H)+: m/z=436.0. 1H NMR (400 MHz, DMSO-d6): δ 8.10 (s, 1H), 7.92 (m, 2H), 7.80 (t, J=8.2 Hz, 1H), 6.77 (t, J=5.9 Hz, 1H), 4.36 (t, J=5.5 Hz, 2H), 3.58 (m, 2H), 3.17 (s, 3H).