Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Mg]Br)C.[CH:5]1([CH2:8][CH3:9])[CH2:7][CH2:6]1.[N:10]([C:13]1[S:14][C:15]2[CH2:16][CH2:17][O:18][C:19]3[CH:26]=[C:25]([Br:27])[CH:24]=[CH:23][C:20]=3[C:21]=2[N:22]=1)=[N+:11]=[N-:12]>C1COCC1>[Br:27][C:25]1[CH:24]=[CH:23][C:20]2[C:21]3[N:22]=[C:13]([N:10]4[C:8]([CH:5]5[CH2:7][CH2:6]5)=[CH:9][N:12]=[N:11]4)[S:14][C:15]=3[CH2:16][CH2:17][O:18][C:19]=2[CH:26]=1
Reactant: [N-]=[N+]=Nc1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: CCC1CC1
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)OCCc1sc(-n3nncc3C3CC3)nc1-2
Temperature: 50 °C
Reaction time: 2 h
Yield: 73.7 %

Procedure:
To a 1M solution of ethylmagnesium bromide in THF (1.3 mL, 1.3 mmol) under a nitrogen atmosphere, was added dropwise cyclopropylethane (70% in toluene, 0.154 mL, 1.3 mmol). The reaction mixture was heated at 50° C. for 15 mins then allowed to cool down to RT. A solution of 2-azido-8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (425 mg, 1.3 mmol) in THF (1.5 mL) was then added dropwise. The reaction mixture was stirred at RT for 2 h, quenched with aqueous saturated ammonium chloride and diluted with ethyl acetate. The organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo. The resultant residue was triturated with 20% ethyl acetate/cyclohexane and filtered to afford the title compound as a pale yellow solid (373 mg, 64%). LCMS 110142391 (Method B): RT=4.40 min, [M+H]+=390. 1H NMR (DMSO-d6): 8.20 (1 H, d, J=8.6 Hz), 7.71 (1 H, d, J=0.7 Hz), 7.36 (1 H, dd, J=8.6, 2.1 Hz), 7.30 (1 H, d, J=2.1 Hz), 4.40 (2 H, t, J=5.0 Hz), 3.41 (2 H, t, J=5.0 Hz), 2.70-2.63 (1 H, m), 1.21-1.15 (2 H, m), 0.91-0.86 (2 H, m).
Reaction SMILES: [C:1]1([CH:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH2:29]O)([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][C:18]=3[OH:28])[C:9]2=[O:31])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:32]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:17]4[CH:22]=[CH:21][C:20]([O:23][C:24]([F:26])([F:25])[F:27])=[CH:19][C:18]=4[O:28][CH2:29]3)[C:9]2=[O:31])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(CO)c1ccc(OC(F)(F)F)cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1cc(OC(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.1 %

Procedure:
To a solution of 1-(diphenylmethyl)-3-(hydroxymethyl)-3-[2-hydroxy-4-(trifluoromethoxy)phenyl]-1,3-dihydro-2H-indol-2-one (17.3 mmol) in anhydrous THF (200 mL) was added triphenylphosphine (6.34 g, 24.2 mmol) followed by diethyl azodicarboxylate (4.39 mL, 24.2 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 16 h, quenched with saturated ammonium chloride (40.0 mL). The aqueous mixture was extracted with ethyl acetate (3×150 mL). The combined organic layers was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography (ethyl acetate/hexane, ¼) to give the title compound (6.00 g, 71%): 1H NMR (300 MHz, CDCl3) δ 7.45-6.51 (m, 18H), 5.08 (d, 1H), 4.81 (d, 1H); MS (ES+) m/z 488 (M+1).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:4]=[C:5]2[CH:13]=[CH:12][CH:11]=[CH:10][N:6]2[C:7](=[O:9])[CH:8]=1.[I:14]N1C(=O)CCC1=O>C(#N)C>[Cl:1][CH2:2][C:3]1[N:4]=[C:5]2[CH:13]=[CH:12][CH:11]=[CH:10][N:6]2[C:7](=[O:9])[C:8]=1[I:14]
Reactant: O=c1cc(CCl)nc2ccccn12
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: O=c1c(I)c(CCl)nc2ccccn12
Temperature: 80 °C
Reaction time: 16 h
Yield: 82.6 %

Procedure:
A mixture of 21.9 g (112.5 mmol) of the product from Step 1 (11) and 38.9 g (168.8 mmol) of N-iodosuccinimide in 660 mL of acetonitrile was stirred at 80° C. under nitrogen for 16 hours. The reaction mixture was then allowed to cool to ambient temperature and the acetonitrile was removed in vacuo. The resulting solid was washed with water, saturated Na2O3S2, saturated NaHCO3, brine, and filtered. Drying under reduced pressure at 40° C. overnight yielded 29.8 g (92.9 mmol, 83%) of 2-(chloromethyl)-3-iodo-4H-pyrido[1,2-a]pyrimidin-4-one (12) as a light brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].[Br:18]N1C(=O)CCC1=O.O.C(=O)(O)[O-].[Na+]>CN(C=O)C>[Br:18][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([CH2:8][CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH:4]=1
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccccc1N
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCc1cc(Br)ccc1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.1 %

Procedure:
To a DMF (50 ml) solution of 1-Amino-2-[2-(tert-butyldimethylsilyloxy)ethyl]benzene (3.96 g, 0.015 mol) [European journal of organic chemistry, 2001, issue 48, 2447-2462] was added N-bromosuccinimide (2.67 g, 0.015 mol) and the mixture was stirred at ambient temperature for 24 hours. Then, the reaction was poured onto saturated aqueous sodium bicarbonate water and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtration and evaporation. The crude material was purified through silica gel column chromatography eluting with hexane/ethyl acetate (10:1 to 5:1) to afford 3.62 g (73% yield) of the title compound as brown oil.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([NH:26]C(OC(C)(C)C)=O)[CH2:7][O:8][C:9]1[C:13]2[CH:14]=[C:15]([NH:18]C(OC(C)(C)C)=O)[CH:16]=[CH:17][C:12]=2[O:11][N:10]=1)(=[O:3])[NH2:2].O1CCOCC1.[ClH:40]>CO>[ClH:40].[NH2:18][C:15]1[CH:16]=[CH:17][C:12]2[O:11][N:10]=[C:9]([O:8][CH2:7][CH:6]([NH2:26])[CH2:5][O:4][C:1](=[O:3])[NH2:2])[C:13]=2[CH:14]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc2onc(OCC(COC(N)=O)NC(=O)OC(C)(C)C)c2c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NC(=O)OCC(N)COc1noc2ccc(N)cc12

Procedure:
To a solution of 0.47 g of 3-(3-carbamoyloxy-2-tert-butoxycarbonylaminopropoxy)-5-tert-butoxycarbonylamino-1,2-benzoisoxazole in 10 ml of methanol is added 5.0 ml of a dioxane solution (2.2N) of hydrogen chloride at 5°-10° C. and they are subjected to reaction at 20°-25° C. overnight. The solvent is removed from the reaction mixture by distillation under reduced pressure, and the residue obtained is crystallized from 2-propanol, after which the crystals are collected by filtration, to obtain 0.21 g of colorless, crystalline 5-amino-3-(2-amino-3-carbamoyloxypropoxy)-1,2-benzoisoxazole hydrochloride having a melting point of 230°-231° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([O:12][C:13]([N:15]1[C@H:22]([CH3:23])[CH2:21][CH2:20][C@H:19]2[C@H:17]([O:18]2)[CH2:16]1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl-].[NH4+]>CO.O>[CH2:5]([O:12][C:13]([N:15]1[CH2:16][C@@H:17]([OH:18])[C@H:19]([N:1]=[N+:2]=[N-:3])[CH2:20][CH2:21][C@H:22]1[CH3:23])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C[C@@H]1CC[C@@H]2O[C@@H]2CN1C(=O)OCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C[C@@H]1CC[C@@H](N=[N+]=[N-])[C@H](O)CN1C(=O)OCc1ccccc1
Yield: 62.9 %

Procedure:
Sodium azide (1.8 g, 27.7 mmol) was added to a (1R,4R,7S)-4-Methyl-8-oxa-3-aza-bicyclo[5.1.0]octane-3-carboxylic acid benzyl ester (2.4 g, 9.2 mmol, Example 1e) and ammonium chloride (1.48 g, 27.7 mmol) in MeOH (16 ml) and H2O (1.6 ml), then was refluxed overnight. The reaction mixture was concentrated in vacuo by rotary evaporation, then was diluted with water (5 ml) and extracted with EtOAc (10 ml). The organic layer was then extracted with water, brine, dried with MgSO4, filtered, concentrated in vacuo by rotary evaporation, and chromatographed (silica gel, 25% EtOAc/hexanes) to yield the title compound (1.76 g, 63%); Liquid chromatgraphy/Electrospray mass spec: M+H+=305.2.
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5](C(O)=O)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]>C(O)CO.O.C(OCC)(=O)C>[Cl:1][C:2]1[NH:6][CH:5]=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Cl)[nH]1
Solvent: CCOC(C)=O
Solvent: OCCO
Solvent: O
Product: O=[N+]([O-])c1cc[nH]c1Cl
Yield: 79.6 %

Procedure:
A stirred solution of 0.34 gram (0.0018 mole) of 5-chloro-4-nitropyrrole-2-carboxylic acid in about 5 mL of ethylene glycol was heated to 190° C. where it was maintained during a one-hour period. After this time the reaction mixture was cooled and diluted with 20 mL of water and 25 mL of ethyl acetate. The organic layer was separated and washed with 25 mL of a solution of 12.5 mL of water and 12.5 mL of an aqueous solution saturated with sodium bicarbonate. The organic layer was then dried with sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel. Elution was accomplished using diethyl ether as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.21 gram of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-])=O)=[CH:31][CH:30]=2)([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=2)[C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].O1CCCC1>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]([C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)([C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)[C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(C(c2ccc([N+](=O)[O-])cc2)(c2ccc([N+](=O)[O-])cc2)c2ccc([N+](=O)[O-])cc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc(C(c2ccc(N)cc2)(c2ccc(N)cc2)c2ccc(N)cc2)cc1

Procedure:
In a Parr reactor, tetrakis(4-nitrophenyl)methane (17.0 grams, 34.0 mmol; prepared as described in Example B) and palladium, weight percent on activated carbon (2.15 grams, 2.00 mmol; obtained from Aldrich Chemical Co., Milwaukee, Wis.) were added to tetrahydrofuran (450 milliliters). The reactor was closed, and the mixture was stirred under 200 pounds per square inch (13.6 atmospheres) of hydrogen pressure for 72 hours at room temperature. The mixture was then filtered through CELITE, solvent was removed from the filtrate by evaporation under reduced pressure, and the resulting white solid was triturated in chloroform. The solid was then recovered by filtration, washed with chloroform again, and dried under reduced pressure at room temperature to give the targeted tetrakis(4-aminophenyl)methane as a white powder in a quantitative yield (12.9 grams).
Reaction SMILES: Cl.O1CCOCC1.[Cl:8][C:9]1[N:10]=[C:11]([C:16]([NH:18][C@H:19]2[CH2:24][CH2:23][N:22]([C:25](OC(C)(C)C)=O)[CH2:21][C@H:20]2[F:32])=[O:17])[NH:12][C:13]=1[CH2:14][CH3:15].BrC1[S:35][C:36]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[C:37]([CH3:39])[N:38]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[Cl:8][C:9]1[N:10]=[C:11]([C:16]([NH:18][C@H:19]2[CH2:24][CH2:23][N:22]([C:25]3[S:35][C:36]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[C:37]([CH3:39])[N:38]=3)[CH2:21][C@H:20]2[F:32])=[O:17])[NH:12][C:13]=1[CH2:14][CH3:15]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2F)nc1Cl
Reactant: CCOC(=O)c1sc(Br)nc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](F)C2)nc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.3 %

Procedure:
A 4 N hydrochloric acid/1,4-dioxane solution (3 mL) was added to tert-butyl cis(±)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-fluoropiperidine-1-carboxylate obtained in Example (196b) (159 mg, 0.424 mmol) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and DMF (4 mL) was added. Ethyl 2-bromo-4-methyl-1,3-thiazole-5-carboxylate (117 mg, 0.467 mmol) and sodium carbonate (225 mg, 2.12 mmol) were added, and the mixture was stirred at 90° C. for three hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and brine, and dried over anhydrous sodium sulfate, and then the insoluble matter was separated by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: hexane:ethyl acetate=1:1 v/v) to obtain 106 mg of the title compound (56%) as a colorless solid.
Reaction SMILES: O[O:2][S:3]([O-:5])=O.[K+].[CH2:7]([O:9][C:10](=[O:26])/[C:11](/[C:18]1[CH:23]=[CH:22][C:21](SC)=[CH:20][CH:19]=1)=[CH:12]/[CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[CH3:8].[CH3:27]C(C)=O>O>[CH2:7]([O:9][C:10](=[O:26])/[C:11](/[C:18]1[CH:23]=[CH:22][C:21]([S:3]([CH3:27])(=[O:5])=[O:2])=[CH:20][CH:19]=1)=[CH:12]/[CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[CH3:8]
Reactant: O=S([O-])OO
Reactant: CCOC(=O)/C(=C/C1CCCC1)c1ccc(SC)cc1
Reactant: CC(C)=O
Agent: [K+]
Solvent: O
Product: CCOC(=O)/C(=C/C1CCCC1)c1ccc(S(C)(=O)=O)cc1
Reaction time: 8 h

Procedure:
Add a suspension of oxone® (113 g, 183 mmol) in water (600 ml) to a solution of (E)-3-cyclopentyl-2-(4-methylsulfanyl-phenyl)-acrylic acid ethyl ester (24.2 g, 83 mmol) in acetone (600 ml). Stir overnight, and then add water (500 ml). Extract the resulting mixture with dichloromethane (2×500 ml). Combine the extracts, wash with brine (2×500 ml), dry over magnesium sulfate, and remove solvent under vacuum to afford the title compound as an off-white solid (25.8 g). MS (m/e): 323.4 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:15][CH2:14][CH2:13][C@@H:12]2[CH2:16][OH:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=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>[NH2:18][C:19]1[CH:24]=[C:23]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([N:11]3[CH2:15][CH2:14][CH2:13][C@@H:12]3[CH2:16][OH:17])(=[O:10])=[O:9])=[CH:4][CH:3]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: O=S(=O)(c1ccc(Br)cc1)N1CCC[C@@H]1CO
Reactant: Nc1cccc(B(O)O)c1
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: CN(C)C=O
Product: Nc1cccc(-c2ccc(S(=O)(=O)N3CCC[C@@H]3CO)cc2)c1
Temperature: 80 °C
Yield: 48.7 %

Procedure:
To a solution of (R)-[1-(4-bromo-benzenesulfonyl)-pyrrolidin-2-yl]-methanol (1.6 g, 5.0 mmol) in DMF (10 mL) was added 3-amino-phenyl boronic acid (0.75 g, 5.5 mmol), Pd(PPh3)4 (45 mg, 0.15 mmol), potassium carbonate (0.75 g, 5.5 mmol) and water (5 mL). The resulting mixture was degassed by gently bubbling argon through the solution for 5 minutes at 20° C. The reaction mixture was then heated at 80° C. overnight. The reaction was filtered through a pad of silica gel, which was washed with CH2Cl2 (25 mL×3). The combined organics were concentrated under reduced pressure to give the crude product, which was washed with EtOAc to give pure (R)-(1-(3′-aminobiphenyl-4-ylsulfonyl)pyrrolidin-2-yl)methanol (C-2) (810 mg, 49%). 1H NMR (300 MHz, CDCl3) δ 7.88 (d, J=8.7 Hz, 2H), 7.70 (d, J=8.7 Hz, 2H), 7.23-7.28 (m, 1H), 6.98 (d, J=7.8 Hz, 1H), 6.91 (d, J=1.8 Hz, 1H), 6.74 (dd, J=7.8, 1.2 Hz, 1H), 3.66-3.77 (m, 3H), 3.45-3.53 (m, 1H), 3.26-3.34 (m, 1H), 1.68-1.88 (m, 3H), 1.45-1.55 (m, 1H). MS (ESI) m/e (M+H+) 333.0.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([NH2:8])=[CH:4][C:5]([NH2:7])=[O:6].N.[CH3:12]NN.Cl>O.C(O)C>[CH3:12][N:8]1[C:3]([C:2]([F:10])([F:9])[F:1])=[CH:4][C:5]([OH:6])=[N:7]1
Reactant: NC(=O)C=C(N)C(F)(F)F
Reactant: CNN
Agent: Cl
Agent: N
Solvent: CCO
Solvent: O
Product: Cn1nc(O)cc1C(F)(F)F
Temperature: 30 °C
Reaction time: 1 h
Yield: 64.3 %

Procedure:
30.82 g (0.2 mol) of 4,4,4-trifluoro-3-amino-2-butenamide (prepared by addition of 2 equivalents of ammonia to the corresponding alkenoic ester) was added to 10.1 g (0.22 mol) of methylhydrazine at room temperature. A slight exotherm raised the temperature to 30° C. The mixture was stirred for 1 hr. at which time the mixture became semi-solid; 10 ml. of ethanol was added to improve stirring. After another 1.5 hr., 7 ml. of ethanol was added, again to aid in stirring the mixture. After a total of 24 hr., the mixture was taken up in 25 ml. of water, the pH was adjusted to 6.5-7.0 with conc. hydrochloric acid (17 ml.), and the precipitated product was collected by filtration and dried to obtain 21.37 g (65.3%) of product m.p. 129°-131° C.
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.C([Si](C)(C)C)#C.[N:12]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[C:14](=[O:20])[CH2:13]2.CO>CCCCC.O1CCCC1>[C:1]([C:14]1([OH:20])[CH:15]2[CH2:18][CH2:19][N:12]([CH2:17][CH2:16]2)[CH2:13]1)#[CH:2]
Reactant: O=C1CN2CCC1CC2
Reactant: [Li]CCCC
Agent: C#C[Si](C)(C)C
Solvent: CO
Solvent: CCCCC
Solvent: C1CCOC1
Product: C#CC1(O)CN2CCC1CC2
Temperature: -70 °C
Reaction time: 1 h

Procedure:
A solution of n-butyl lithium (100 ml of a 2M solution in pentane) was added portion-wise over a period of 20 minutes to a stirred solution of ethynyltrimethylsilane (19.6 g) in dry tetrahydrofuran (400 ml) at -70° C. The mixture was stirred for 1 hour at -70° C. A solution of 3-quinuclidinone (2.4 g) in dry tetrahydrofuran (100 ml) was then added and the mixture stirred for 1 hour at -70° C. Methanol (1 ml) was then added to the mixture and the mixture allowed to warm to ambient temperature. The solvents were removed by evaporation. Methanol (500 ml) and potassium carbonate (40 g) were added to the residue and the mixture was stirred for 1 hour. The solvent was removed by evaporation. The residue was triturated with water (500 ml) and then dried in vacuo to give 3-ethynyl-3-hydroxy-quinuclidine as a solid, m.p. 193°-197° C.; NMR(DMSO-d6): 1.5-1.3(1H,m), 1.4-1.6(1H,m), 1.7-1.95(3H,m), 2.55-2.8(5H,m), 2.95(1H,d), 3.3(1H,d) and 5.4(1H,s); m/z 152 (M+H).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]([N+:12]([O-])=O)[CH:8]=[CH:9][C:10]=1[CH3:11])(=[O:4])=[O:3]>ClCCl.CO.[Pd]>[NH2:1][S:2]([C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][C:10]=1[CH3:11])[NH2:12])(=[O:3])=[O:4]
Reactant: Cc1ccc([N+](=O)[O-])cc1S(N)(=O)=O
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(N)cc1S(N)(=O)=O
Reaction time: 0.25 h

Procedure:
To a solution of 3-aminosulfonyl-4-methylnitrobenzene in dichloromethane and methanol was added 10% Pd/C and the mixture shaken under a hydrogen atmosphere at 50 psi for 15 minutes. The mixture was filtered through diatomaceous earth and the filter cake was washed with methanol. The combined organic solvents were concentrated under reduced pressure to give crude product, which was further purified by flash column chromatography (ethyl acetate:hexanes 1:1) to give 3-aminosulfonyl-4-methylaniline, LCMS: purity: 87%; MS (m/e): 187 (MH+).
Reaction SMILES: Br[C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:11](=[O:14])([O-])[O-].[K+].[K+].O>CS(C)=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[N+:8]([C:3]1[C:2]([N:4]2[CH2:5][CH2:11][O:14][CH2:2][CH2:3]2)=[CH:7][CH:6]=[CH:5][N:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ncccc1Br
Reactant: O=C([O-])[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ncccc1N1CCOCC1

Procedure:
To a solution of 3-bromo-2-nitropyridine (207 mg, 1 mmol) in DMSO (2 mL) was added at room temperature under stirring and under an atmosphere of nitrogen morpholine (95.8 mg, 95.8 μL, 1.1 mmol), tetrabutyl ammonium iodide (18.5 mg, 50.0 μmol) and potassium carbonate (152 mg, 1.1 mmol). The reaction was stirred at 80° C. over night. Water was added and the aqueous phase was extracted twice with diethyl ether. The combined organic layers were washed with water and with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The title compound was obtained as a yellow oil (57 mg, 27%) after column chromatography on silica gel using a gradient from heptane/ethyl acetate 4:1 to 1:1 (v/v) as eluent.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[CH2:12][CH3:13])[CH2:8][C:7]([NH:15][C:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:14])[CH2:6]2)[CH3:2].C(NC1CC2C(=CC(CC)=C(CC)C=2)C1)C1C=CC=CC=1>>[CH2:16]([NH:15][C:7]1([CH3:14])[CH2:8][C:9]2[C:5](=[CH:4][C:3]([CH2:1][CH3:2])=[C:11]([CH2:12][CH3:13])[CH:10]=2)[CH2:6]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCc1cc2c(cc1CC)CC(C)(NC(=O)c1ccccc1)C2
Agent: CCc1cc2c(cc1CC)CC(NCc1ccccc1)C2
Product: CCc1cc2c(cc1CC)CC(C)(NCc1ccccc1)C2

Procedure:
Benzyl-(5,6-diethyl-2-methyl-indan-2-yl)-amine is prepared from N-(5,6-diethyl-2-methyl-indan-2-yl)-benzamide by an analogous procedure to that used to prepare benzyl-(5,6-diethyl-indan-2-yl)-amine in Intermediate 18. ES+MS m/e 294 (MH+)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1)#[N:2].[C:12]1([NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18].Br[CH:21]([C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=1)[CH3:22].C(=O)([O-])[O-].[K+].[K+]>C(OCC)C.CN(C=O)C>[C:27]([C:26]1[CH:30]=[CH:31][C:23]([CH:21]([NH:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:19][C:10](=[O:11])[NH:9][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)[CH3:22])=[CH:24][CH:25]=1)([OH:29])=[O:28]
Reactant: CC(Br)c1ccc(C(=O)O)cc1
Reactant: Nc1ccccc1N
Reactant: N#Cc1ccc(N=C=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(Nc1ccccc1NC(=O)Nc1ccc(C#N)cc1)c1ccc(C(=O)O)cc1

Procedure:
12.8 g (88.8 mmol) 4-cyanophenylisocyanat were dissolved in 500 ml diethyl ether at rt. 9.6 g (88.8 mmol) o-phenylene diamine were added with stirring. After stirring overnight, the reaction mixture was filtrated and the solid washed with diethylether. The so prepared mono-urea derivative was sufficient pure for further reactions. 3.78 (15 mmol) were dissolved in 30 ml anhydrous dry DMF, 3.44 g (15 mmol) 4-(1-bromoethyl)-benzoic acid and 2 g potassium carbonate were added and stirred for 3 days at rt. The solvent was removed under reduced pressure, the product dissolved in ethyl acetate and extracted with 1 m HCl, water and brine. The organic phase was dried over sodium sulfate and the solvent removed under reduced pressure.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].C([Li])CCC.[CH3:15][N:16]1[CH:20]2[CH2:21][C:22]([CH2:24][CH:17]1[CH2:18][CH2:19]2)=[O:23].O>C(OCC)C>[OH:23][C:22]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[O:8][CH3:9])[CH2:21][CH:20]2[N:16]([CH3:15])[CH:17]([CH2:18][CH2:19]2)[CH2:24]1
Reactant: COc1ccccc1Br
Reactant: CN1C2CCC1CC(=O)C2
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: COc1ccccc1C1(O)CC2CCC(C1)N2C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of 2-bromoanisole (9.25 ml, 0.074 mol) in dry diethyl ether (110 ml) under argon was cooled to 0° C. and was treated with n-butyllithium (1.6M) (45.6 ml, 0.073 mol) slowly. The reaction mixture was then allowed to warm to room temp. After 0.5 h, a solution of tropinone (10.14 g, 0.073 mol) in dry diethyl ether (60 ml) was added causing the reaction mixture to reflux. Reflux was maintained for a further 0.5 h, before the reaction mixture was allowed to cool. Water (40 ml) was then added and the reaction mixture was stirred for 0.25 h. The organic layer was then separated, dried (Na2SO4) and evaporated under reduced pressure to give a pale yellow oily solid, which was triturated with petroleum ether (60-80). The resultant suspension was then filtered to give the title compound as a white solid, which was dried in vacuo (9.04 g, 50%).