Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:13]=[C:12]([C:14]([OH:16])=[O:15])[CH:11]=[C:10]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:9]=1>CN(C=O)C.C(Cl)(Cl)Cl>[Cl:7][C:8]1[CH:13]=[C:12]([C:14]([O:16][CH3:1])=[O:15])[CH:11]=[C:10]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:9]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(Cl)nc(OCc2ccccc2)c1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)nc(OCc2ccccc2)c1
Reaction time: 1 h

Procedure:
With cooling with ice, oxalyl chloride (5.8 mL) and DMF (3 drops) were added to a CHCl3 (40 mL) solution of 2-chloro-6-benzyloxypyridine-4-carboxylic acid, and stirred at that temperature for 1 hour. DMF (3 drops) was added to it, and stirred overnight at room temperature, then oxalyl chloride (2.9 mL) and DMF (3 drops) were added to it, and stirred at room temperature for 3 hours. The solvent was evaporated away, CHCl3-MeOH was added to the residue, and stirred at room temperature for 30 minutes. Sodium bicarbonate water was added to the reaction solution, extracted with chloroform, and the organic layer was washed with water, saturated sodium bicarbonate water and saturated saline water, and dried with anhydrous sodium sulfate. This was filtered, concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound as a yellow oil.
Reaction SMILES: [ClH:1].[Cl-:2].[NH2:3][C:4]([CH3:14])([CH3:13])[CH2:5][CH2:6][N+:7]1([CH3:12])[CH2:11][CH2:10][CH2:9][CH2:8]1.C(O[Cl:20])(C)(C)C>CO.O>[Cl-:20].[Cl:1][N:3]([Cl:2])[C:4]([CH3:14])([CH3:13])[CH2:5][CH2:6][N+:7]1([CH3:12])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CC(C)(N)CC[N+]1(C)CCCC1
Reactant: CC(C)(C)OCl
Reactant: Cl
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: CC(C)(CC[N+]1(C)CCCC1)N(Cl)Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-(3-amino-3-methylbutyl)-1-methylpyrrolidinium chloride hydrochloride (1.07 g, 4.4 mmol) in a mixture of methanol (15 mL) and water (10 mL) was cooled in an ice bath for 15 min. t-BuOCl (1.56 mL, 3 equiv, 13.2 mmol) was added in one portion via syringe to the colorless solution to give a deep yellow solution. The reaction mixture was stirred for 30 min at 0° C., then concentrated under reduced pressure to yield a colorless oil. This oil was dissolved into water and purified via reverse phase chromatography on a Shimadzu Prep-LC utilizing water/acetonitrile and 0.05% acetic acid as modifier. Fractions were collected monitoring UV absorbance at 215 nm. Fractions were pooled and lyophilized to give a pale yellow foam, (0.94 g, 77.6%). 1H NMR (D2O, 400 MHz): δ 1.44 (s, 6H), 2.17 (m, 4H), 2.17-2.32 (m, 2H), 3.06 (s, 3 H), 3.45-3.60 (m, 6H). LRMS (ESI+) for C10H21Cl2N2+ (239.1); Found: 239, 241 (M+, M2H+).
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([CH:7]([N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32](Cl)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(#N)C>[Cl-:25].[C:1]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:2]=[CH:3][C:4]([CH:7]([N+:14]2[CH:18]=[CH:17][N:16]([C:32]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[Cl:25])([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH:15]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:5][CH:6]=1
Reactant: c1ccc(-c2ccc(C(c3ccccc3)n3ccnc3)cc2)cc1
Reactant: Clc1ccccc1C(Cl)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: Clc1ccccc1C(c1ccccc1)(c1ccccc1)n1cc[n+](C(c2ccccc2)c2ccc(-c3ccccc3)cc2)c1
Product: [Cl-]
Temperature: 80 °C
Yield: 83.4 %

Procedure:
15.1 g (0.05 mol) of 1-[α-(4-biphenylyl)-benzyl]-imidazole and 15.2 g (0.05 mol) of 2-chlorophenyl-diphenylmethyl chloride are suspended in 400 ml of acetonitrile and the suspension is heated to 80° C. for 24 hours. It is then filtered and the filtrate is concentrated by distilling off the solvent. The residue crystallises after trituration with ether. 13 g (42% of theory) of 1-[α-(4-biphenylyl)-benzyl]-3-(2-chlorophenyl-diphenyl-methyl)-imidazolium chloride of melting point 140° C. (with decomposition) are obtained.
Reaction SMILES: [F:1][C:2]([CH3:12])([CH3:11])[CH2:3][C:4]1([OH:10])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[S:13]1[C:17]2=[CH:18][CH:19]=[CH:20][C:21]([S:22]([NH:25][C:26]3[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=3)(=[O:24])=[O:23])=[C:16]2[N:15]=[CH:14]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[F:1][C:2]([CH3:12])([CH3:11])[CH2:3][C:4]1([OH:10])[CH2:5][CH2:6][N:7]([C:30]([C:29]2[CH:28]=[CH:27][C:26]([NH:25][S:22]([C:21]3[CH:20]=[CH:19][CH:18]=[C:17]4[S:13][CH:14]=[N:15][C:16]=34)(=[O:24])=[O:23])=[CH:34][CH:33]=2)=[O:31])[CH2:8][CH2:9]1
Reactant: O=C(O)c1ccc(NS(=O)(=O)c2cccc3scnc23)cc1
Reactant: CC(C)(F)CC1(O)CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(F)CC1(O)CCN(C(=O)c2ccc(NS(=O)(=O)c3cccc4scnc34)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a round-bottom flask was added with 4-(2-fluoro-2-methylpropyl) piperidin-4-ol (25 mg 0.143 mmol), 4-(benzo[d]thiazole-4-sulfonamido)benzoic acid (47 mg, 0.143 mmol), DIPEA (110 mg, 0.85 mmol), HATU (54 mg, 0.143 mmol), and DCM (5 mL). The mixture was stirred at r.t. for 16 hours. After washing with satd. NaHCO3, brine, the combined organic layer was dried over anhy. Na2SO4 and concentrated in vacuo. Purification by a standard method gave the desired compound. 1H NMR (CHLOROFORM-d) δ: 9.31 (s, 1H), 8.19 (dd, J=8.1, 0.8 Hz, 1H), 8.10 (dd, J=7.5, 1.1 Hz, 1H), 7.93 (s, 1H), 7.54 (t, J=7.9 Hz, 1H), 7.16-7.23 (m, J=8.3 Hz, 2H), 7.05-7.15 (m, J=8.3 Hz, 2H), 4.19-4.47 (m, 1H), 3.46 (d, J=15.6 Hz, 1H), 3.35 (d, J=15.3 Hz, 2H), 1.89 (s, 3H), 1.84 (s, 3H), 1.49-1.55 (m, 3H), 1.46 (s, 3H). LC-MS: m/z 492.65 (M+H)+
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:29]=[CH:28][C:9]3[C:10]4[N:11]=[C:12]([C:18]5[N:19]([CH2:23][C:24]([F:27])([F:26])[F:25])[N:20]=[CH:21][N:22]=5)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O.Br[CH2:42][CH2:43][OH:44]>O.C(OCC)(=O)C>[F:27][C:24]([F:26])([F:25])[CH2:23][N:19]1[C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:3]=[N:2][N:1]([CH2:42][CH2:43][OH:44])[CH:5]=5)[CH:29]=[CH:28][C:9]=4[C:10]=3[N:11]=2)=[N:22][CH:21]=[N:20]1
Reactant: FC(F)(F)Cn1ncnc1-c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: OCCn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)cn1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A solution of 8-(1H-Pyrazol-4-yl)-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (0.30 g, 0.00072 mol) and Cesium Carbonate (0.28 g, 0.00086 mol) in N,N-Dimethylformamide (1.5 mL, 0.019 mol) was stirred at room temperature for 5 minutes. 2-Bromoethanol (0.061 mL, 0.00086 mol) was added and the reaction was stirred at 70° C. overnight. The mixture was cooled to room temperature and ethyl acetate and water were added to the reaction. The aqueous layer was extracted 3 times with ethyl acetate and the combined organics were washed with water, dried with MgSO4, and concentrated. The crude was purified by reverse-phase HPLC to give (48.4 mg) as a colorless solid. MS (ESI+) 463.1. 1H NMR (400 MHz, DMSO) δ 8.29 (s, 1H), 8.27 (d, J=8.3, 1H), 8.24 (s, 1H), 7.97 (s, 1H), 7.44 (dd, J=8.3, 1.6, 1H), 7.31 (d, J=1.5, 1H), 5.86 (q, J=8.7, 2H), 4.91 (t, J=5.3, 1H), 4.40 (t, J=4.9, 2H), 4.16 (t, J=5.6, 2H), 3.77 (q, J=5.6, 2H), 3.47 (t, J=4.9, 2H)
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[H-].[Na+].[Si:12](Cl)([C:15](C)(C)C)([CH3:14])[CH3:13]>C1COCC1>[CH3:13][Si:12]([CH3:15])([CH3:14])[O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:9]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)OCCCCCCCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1,7-heptandiol (44 mmol) in THF (15 mL) is cooled to 0° C. and treated with sodium hydride (44 mmol) followed by tert-butyldimethylsilyl chloride (44 mmol). The reaction mixture is stirred at room temperature overnight. Concentration in vacuo and flash chromatography affords 7-trimethylsiloxy-1-heptanol . To a solution of 7-trimethylsiloxy-1-heptanol (11.6 mmol) in dry dichloromethane (50 mL) is added 2,6-di-tert-butyl-4-methylpyridine (4.6 g, 22.2 mmol) and triflic anhydride (3.7 mL, 22.2 mmol) at 0° C. The reaction is stirred at room temperature for 20 min, poured into water, and extracted with dichloromethane. The combined extracts are dried over anhydrous sodium sulfate and concentrated in vacuo and to afford 7-trimethylsiloxy-1-heptyl triflate (50) which is used without further purification.
Reaction SMILES: CS[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]2=[N:11][C:10]=1[CH:20]([N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32])[CH3:21].O[O:34][S:35]([O-:37])=O.[K+].[CH2:39]1COCC1>O>[CH3:39][S:35]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:3][C:4]=1[C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]2=[N:11][C:10]=1[CH:20]([N:22]1[C:23](=[O:32])[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:30]1=[O:31])[CH3:21])(=[O:37])=[O:34]
Reactant: C1CCOC1
Reactant: O=S([O-])OO
Reactant: CSc1ccccc1-c1c(C(C)N2C(=O)c3ccccc3C2=O)nc2ccccn2c1=O
Agent: [K+]
Solvent: O
Product: CC(c1nc2ccccn2c(=O)c1-c1ccccc1S(C)(=O)=O)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of 2-(1-(3-(2-(methylthio)phenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)ethyl)isoindoline-1,3-dione (0.4278 g, 0.969 mmol) in THF (7.27 mL) and water (2.422 mL) was added oxone (1.489 g, 2.422 mmol) and the mixture was stirred at rt. After 24 h, LC-MS (ESI) and HPLC showed that the reaction was complete and no reactant remained. After 26 h, to the mixture was added water (50 mL) and the resulting precipitate was filtered and washed with water (50 mL) to give 2-(1-(3-(2-(methylsulfonyl)phenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)ethyl)isoindoline-1,3-dione as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.99 (1 H, ddd, J=7.0, 1.6, 0.8 Hz), 8.01-8.11 (2 H, m), 7.69-7.86 (5 H, m), 7.56 (1 H, td, J=7.8, 1.3 Hz), 7.46 (1 H, td, J=6.9, 1.4 Hz), 7.29 (1 H, td, J=7.5, 1.4 Hz), 7.09 (1 H, dd, J=7.6, 1.2 Hz), 5.37-5.46 (1 H, m), 3.03 (3 H, s), 1.60 (3 H, d, J=7.0 Hz); Mass Spectrum (ESI) a major peak of m/e=474.1 (M+1).
Reaction SMILES: [CH2:1]([C@H:4]1[N:7]([C:8](=[C:13]([CH3:15])[CH3:14])[C:9]([O:11][CH3:12])=[O:10])[C:6](=[O:16])[C@@H:5]1[N:17]1C(=O)C2=CC=CC=C2C1=O)[CH:2]=[CH2:3].CN(C)CCCN>C(Cl)Cl.CO>[NH2:17][CH:5]1[C@@H:4]([CH2:1][CH:2]=[CH2:3])[N:7]([C:8](=[C:13]([CH3:15])[CH3:14])[C:9]([O:11][CH3:12])=[O:10])[C:6]1=[O:16]
Reactant: C=CC[C@@H]1[C@@H](N2C(=O)c3ccccc3C2=O)C(=O)N1C(C(=O)OC)=C(C)C
Agent: CN(C)CCCN
Solvent: CO
Solvent: ClCCl
Product: C=CC[C@@H]1C(N)C(=O)N1C(C(=O)OC)=C(C)C
Reaction time: 24 h
Yield: 51.1 %

Procedure:
To a solution of methyl 2-[(3R,4R)-4-allyl-3-phthalimido-2-oxoazetidin-1-yl]-3-methyl-2-butenoate (2.64 g) in a mixture of methylene chloride (20 ml) and methanol (10 ml) was added N,N-dimethyl-1,3-propanediamine (1.98 ml) and the mixture was left in a refrigerator for 3 days and at room temperature for 24 hours. The reaction mixture was evaporated and the residue was dissolved in ethyl acetate (50 ml), washed with water, dried over magnesium sulfate and evaporated to give an oil, which was chromatographed on silica gel eluting with a mixture of methylene chloride and acetone (6-5:1) to give methyl 2-[(4R)-3-amino-4-allyl-2-oxoazetidin-1-yl]-3-methyl-2-butenoate (873 mg) as an oil.
Reaction SMILES: [OH-].[K+].Cl[C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[N:7]=[CH:6][N:5]=1.[OH:18][C:19]1[CH:24]=[C:23]([OH:25])[CH:22]=[CH:21][C:20]=1[CH3:26]>O>[CH3:15][O:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][C:10]=1[O:16][CH3:17])[N:7]=[CH:6][N:5]=[C:4]2[O:25][C:23]1[CH:22]=[CH:21][C:20]([CH3:26])=[C:19]([OH:18])[CH:24]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Cc1ccc(O)cc1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1cc2ncnc(Oc3ccc(C)c(O)c3)c2cc1OC
Temperature: 140 °C
Reaction time: 0.25 h
Yield: 33.8 %

Procedure:
Solid potassium hydroxide (71 mg, 1.2 mmol) and then 4-chloro-6,7-dimethoxyquinazoline (0.25 g, 1.1 mmol), (prepared as described for the starting material in Example 1), were added to a melt of 2,4-dihydroxytoluene (0.6 g, 4.8 mmol) at 140° C. The mixture was stirred at 140° C. for 15 minutes, then allowed to cool. The mixture was diluted with water, and acidified to pH4 then extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and the solvent removed by evaporation. The crude product was first purified by flash chromatography eluting with petroleum ether/ethyl acetate (1/9) and then by absorption HPLC eluting with trichloromethane/acetonitrile (85/15) to give 6,7-dimethoxy-4-(3-hydroxy-4-methylphenoxy)quinazoline (116 mg, 34%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][C@@H:8]([CH2:12][NH:13][C:14](=[O:25])OC2C=CC([N+]([O-])=O)=CC=2)[CH2:7]1.[CH2:30]([NH2:33])[C:31]#[CH:32].ClCCl>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][C@@H:8]([CH2:12][NH:13][C:14]([NH:33][CH2:30][C:31]#[CH:32])=[O:25])[CH2:7]1
Reactant: C#CCN
Reactant: O=C(NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCNC(=O)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Yield: 79.1 %

Procedure:
Example 57 was prepared in an analogous manner to Example 43 from Intermediate 13 (0.1 g) and propargylamine (0.014 g) using dichloromethane and triethylamine at a temperature of 22° C. to yield the title compound (0.064 g).
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)[CH2:2]1.[NH:16]1[CH:20]=[CH:19][N:18]=[CH:17]1.[Na].C(OCC)(=O)C>CN(C)C=O>[OH:1][C:3]1([CH2:2][N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Reactant: c1c[nH]cn1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(O)(Cn2ccnc2)CC1
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 87.9 %

Procedure:
4.25 g of tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate was dissolved in 30 ml dimethylformamide, 5.38 g of sodium imidazole was added thereto, and the mixture was stirred at 60° C. for 3 hr and 40 min. After cooling, ethyl acetate was added to the reaction solution, and it was washed with water for 3 times and then with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated and subjected to silica gel column chromatography to give 4.93 g of tert-butyl 4-hydroxy-4-(1H-1-imidazolylmethyl)-1-piperidinecarboxylate.
Reaction SMILES: C1(C)C=CC(S([O-])=O)=CC=1.[Na+].[CH2:12]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](C=O)=[C:15]1[CH3:25])[CH3:13]>>[CH2:12]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]1[CH3:25])[CH3:13]
Reactant: CCn1c(C)c(C=O)c2ccccc21
Agent: Cc1ccc(S(=O)[O-])cc1
Agent: [Na+]
Product: CCn1c(C)cc2ccccc21

Procedure:
Following a procedure similar to that described in Example 4A but employing 6.5 g. of 85.9% sodium p-toluenesulfinate 4.6 g. of 1-ethyl-2-methyl-1H-indole-3-carboxaldehyde and 3.8 g. of 1-ethyl-2-methyl-1H-indole there was obtained 4.5 g. of 3-[(1-ehtyl-2-methyl-1H-indol-3-yl)(4-methylphenylsulfonyl)methyl]-1-ethyl-2-methyl-1H-indole, m.p. 146°-152° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][N:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:5][CH:4]=[CH:3]1.N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>C(Cl)Cl.CCOCC.O>[Si:18]([O:1][CH:2]1[CH2:7][N:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:5][CH:4]=[CH:3]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)N1CC=CC(O)C1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)N1CC=CC(O[Si](C)(C)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
To a solution of Compound 239C (16 g, 93.5 mmol) in 150 mL of dry CH2Cl2 at 0° C. was added imidazole (9.5 g, 140.0 mmol) and t-butyldimethylsilylchloride (15.5 g, 102.8 mmol) and the mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with ether (500 mL) and water (1 L) at 0° C. The organic phase was separated and washed with 10% LiCl (150 mL×3), dried over anhydrous MgSO4. Concentration in vacuo followed by flash chromatography (hexane-EtOAc: 15:1 to 10:1) afforded 25.2 g (Yield: 94.4%) of 239D as an oil.
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]#[N:17])=[CH:13][CH:14]=2)[C:9]([C:18]2[CH:22]=[CH:21][S:20][CH:19]=2)=[N:8]1.[N:23]([Sn](CCCC)(CCCC)CCCC)=[N+:24]=[N-:25].O1CCOCC1.Cl>C1(C)C=CC=CC=1.O1CCCC1>[N:23]1[NH:24][N:25]=[N:17][C:16]=1[C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[NH:7][N:8]=[C:9]2[C:18]1[CH:22]=[CH:21][S:20][CH:19]=1
Reactant: N#Cc1ccc2c(c1)c(-c1ccsc1)nn2C1CCCCO1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Agent: Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: c1cc(-c2n[nH]c3ccc(-c4nn[nH]n4)cc23)cs1

Procedure:
The title compound was prepared from 1-perhydro-2H-pyran-2-yl-3-(3-thienyl)-1H-indazole-5-carbonitrile (0.233 g, 0.75 mmol), azidotributyl tin (0.375 g, 0.3 10 mL, 1.13 mmol) in toluene (10 mL) as described for the preparation of Example 167. Deprotection was effected by treating a dioxane solution (5 mL) with 5 mL of 6.0N aqueous solution of hydrogen chloride. The solid obtained upon completion of the reaction was partially dissolved in 3 mL of tetrahydrofuran and was precipitated out by adding 20 mL of hexanes (0.108 g, 0.85 mmol, 79% yield over 2 steps): 1H NMR (DMSO-d6) δ 13.5 (br s, 1H), 8.8 (s, 1H), 8.2 (t, 1H), 8.1 (dd, 1H), 7.8–7.7 (m, 3H); ES-MS (m/z) 269 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([O:23][CH3:24])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[S:44]1[CH:48]=[CH:47][N:46]=[C:45]1[C@H:49]([NH2:51])[CH3:50]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:36]([NH:51][C@@H:49]([C:45]2[S:44][CH:48]=[CH:47][N:46]=2)[CH3:50])=[O:42])=[C:18]([O:23][CH3:24])[CH:17]=1
Reactant: C[C@@H](N)c1nccs1
Reactant: COc1cc(Oc2ccnc3cc(OC)c(OC)cc23)ccc1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc(Oc2ccnc3cc(OC)c(OC)cc23)ccc1NC(=O)N[C@H](C)c1nccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methoxyaniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of (1R)-1-(1,3-thiazol-2-yl)-1-ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (36 mg, yield 82%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[C:1]1([CH2:7][CH2:8][NH:9][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: NCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccccc1NCCc1ccccc1
Temperature: 100 °C
Yield: 97 %

Procedure:
A mass of 4.8 g (0.04 mol) of 2-phenylethylamine was added dropwise, at ambient temperature, to a mixture of 5.6 g (0.04 mol) of 2-fluoronitrobenzene and 11.06 g (0.08 mol) of anhydrous potassium carbonate in 30 ml of DMSO. The mixture was heated at 100° C. for 3 hours. The mixture was then cooled to ambient temperature and was added to 100 ml of water, which resulted in the precipitation of a light orange compound. The solid was recovered by filtration and dried using a desiccator at reduced pressure. A mass of 9.4 g of orange crystals was obtained with a yield of 98%. The melting point found was coherent with the theoretical value, i.e. 64-66° C.
Reaction SMILES: CCOCC.[CH2:6]([Mg]Cl)[CH2:7][CH3:8].[C:11]([N:16]1[C@H:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:19][O:18][C:17]1=[O:27])(=[O:15])[CH:12]=[CH:13][CH3:14]>C1COCC1>[CH3:14][C@H:13]([CH2:6][CH2:7][CH3:8])[CH2:12][C:11]([N:16]1[C@H:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:19][O:18][C:17]1=[O:27])=[O:15]
Reactant: CC=CC(=O)N1C(=O)OC[C@H]1c1ccccc1
Reactant: CCC[Mg]Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC[C@@H](C)CC(=O)N1C(=O)OC[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.7 %

Procedure:
To the copper (1) bromide dimethylsulfide complex (13.34 g, 64.87 mmol) in dry THF (150 mL) at −30° C. under Nitrogen was added a 2M ether solution of Propylmagnesiumchloride (64.87 mL, 129.7 mmol) and stirred for 20 minutes. (R)-3-But-2-enoyl-4-phenyl-oxazolidin-2-one (15.0 g, 64.87 mmol) in THF (60 mL) was added over a 15 minute period at −35° C. and let slowly warm up to room temperature over 4 hours. The mixture was cooled to 0° C. and quenched with saturated ammonium chloride solution. The suspension was extracted into ether, washed with 5% ammonium hydroxide solution and then with brine and dried over MgSO4. The solution was concentrated under reduced pressure to afford the titled compound (13.34 g; 100% yield) as a white solid: 1H NMR (400 MHz, CDCl3) δ ppm 0.8 (m, 6 H) 1.2 (m, 3 H) 1.6 (s, 1 H) 2.0 (m, 1 H) 2.7 (dd, J=16.1, 8.5 Hz, 1 H) 3.0 (dd, J=15.9, 5.4 Hz, 1 H) 4.3 (dd, J=8.9, 3.8 Hz, 1 H) 4.7 (t, J=8.9 Hz, 1 H) 5.4 (dd, J=8.8, 3.9 Hz, 1 H) 5.4 (dd, J=8.8, 3.9 Hz, 1 H) 7.3 (m, 5 H). MS, m/z (relative intensity): 276 [M+1H, 100%].
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:7]([CH2:14][CH2:15]Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O1CCCC1>[O:7]([CH2:14][CH2:15][N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C1CNCCN1
Reactant: BrCCOc1ccccc1
Solvent: C1CCOC1
Product: c1ccc(OCCN2CCNCC2)cc1
Temperature: 50 °C
Reaction time: 36 h
Yield: 64.7 %

Procedure:
Piperazine (2.15 g) and 2-phenoxyethyl bromide (1.00 g) were dissolved in tetrahydrofuran (30 ml), and the mixture was stirred at 40 to 60° C. for 36 hours. The reaction solution was evaporated, and aqueous saturated sodium bicarbonate and diethyl ether were added to the residue, and the aqueous layer was partitioned. Methylene chloride was added to the aqueous layer, and the organic layer was partitioned. The organic layer was dried over sodium sulfate anhydrous and evaporated, whereby the title compound (664 mg, 65%) was obtained.