Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH2:4][CH2:5][C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH2:3]>[Pd].C(O)C>[CH3:1][CH:2]([CH3:3])[CH2:4][CH2:5][C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: C=C(C)CCc1cc2ccccc2[nH]1
Agent: [Pd]
Solvent: CCO
Product: CC(C)CCc1cc2ccccc2[nH]1
Reaction time: 2 h
Yield: 59 %

Procedure:
Into a 3-necked round bottom flask under a blanket of nitrogen was placed 5% palladium catalyst on charcoal (771 mg). A solution of 2-(2-methyl-1-buten-4-yl) indole (671 mg) in ethanol (36 ml) was added to the flask, which was evacuated and charged with hydrogen twice. The mixture was stirred vigorously under hydrogen (1 atmosphere) for 2 hours, followed by filtration through a pad of Celite. The solvent was removed under reduced pressure and the crude residue was purified by flash chromatography (3% ethyl acetate/hexane) to give 2-(3-methyl-n-butyl)indole (400 mg, 59%) as a yellow crystalline solid.
Reaction SMILES: CN[C:3]([O:5][CH:6]1[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:13][C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)=O.[CH2:20](O)[C:21]#C>>[CH:18]1[C:19]2[CH:6]([O:5][CH2:3][C:20]#[CH:21])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:13][C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: CNC(=O)OC1c2ccccc2Oc2ccccc21
Reactant: C#CCO
Product: C#CCOC1c2ccccc2Oc2ccccc21

Procedure:
9-(N-Methylcarbamoyloxy)xanthene (3.0 g., 11.8 mmoles.) was stirred with 18 ml. of propargyl alcohol for 1.5 hours at room temperature, and the mixture was then filtered. The filtrate was evaporated in vacuo, and the residue was dissolved in ice-cold ether and washed twice with 20 ml. of ice-cold 10% aqueous acetic acid, 15 ml. of ice-cold water, and 10 ml. of ice-cold 5% aqueous sodium bicarbonate solution. After drying over potassium carbonate, the solvent was removed in vacuo. The resulting solid was recrystallized from hexane to give propargyl 9-xanthenyl ether, m.p. 74°-76°C.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C:3](=[O:8])[C:4](Cl)=[N:5][OH:6].[CH2:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])O.[K+]>C1(C)C=CC=CC=1.O>[CH3:1][N:2]([CH3:9])[C:3]([C:4]1[CH2:10][CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:6][N:5]=1)=[O:8]
Reactant: CN(C)C(=O)C(Cl)=NO
Reactant: C=Cc1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CN(C)C(=O)C1=NOC(c2ccccc2)C1
Reaction time: 0.17 h

Procedure:
To a solution of 2-(dimethylamino)-N-hydroxy-2-oxoethanimidoyl chloride (prepared according to the procedure of E. Raleigh, U.S. Pat. No. 3,557,089) (6.0 g, 40 mmol) and styrene (6.0 g, 60 mmol) in toluene (15 mL) was added a solution of potassium hydrogen carbonate (5.0 g, 50 mmol) in water (25 mL) over 1 h, while keeping the reaction temperature between 7 and 10° C. The reaction mixture was diluted with 10 mL of toluene and stirred for an additional 10 minutes. The organic layer was separated and washed with water. The organic layer was concentrated under reduced pressure until no styrene remained to give 8.7 g of the title compound as a light yellow oil. This compound was of sufficient purity to use in subsequent reactions.
Reaction SMILES: [CH2:1]([C@:3]1([CH2:29][CH2:30][CH2:31][CH2:32][B:33]2[O:37][C:36]([CH3:39])([CH3:38])[C:35]([CH3:41])([CH3:40])[O:34]2)[C:8](=[O:9])[O:7][C@@H:6](C2C=CC=CC=2)[C@@H](C2C=CC=CC=2)[N:4]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH3:2].C(=O)=O.N.[Li]>CC#N.C1COCC1>[C:25]([O:24][C:22]([NH:4][C@@:3]([CH2:1][CH3:2])([CH2:29][CH2:30][CH2:31][CH2:32][B:33]1[O:34][C:35]([CH3:41])([CH3:40])[C:36]([CH3:39])([CH3:38])[O:37]1)[C:8]([O:7][CH3:6])=[O:9])=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC[C@]1(CCCCB2OC(C)(C)C(C)(C)O2)C(=O)O[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1C(=O)OC(C)(C)C
Agent: N
Agent: O=C=O
Agent: [Li]
Solvent: CC#N
Solvent: C1CCOC1
Product: CC[C@@](CCCCB1OC(C)(C)C(C)(C)O1)(NC(=O)OC(C)(C)C)C(=O)OC
Temperature: -78 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
A three-necked round-bottomed flask equipped with nitrogen inlet tube and dry ice condenser was charged with (3S,5R,6S)-tert-butyl 3-ethyl-2-oxo-5,6-diphenyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)morpholine-4-carboxylate (0.57 g, 1.01 mmol) and THF (1 mL). After cooling the condenser to −78° C. and the flask to −45° C. (CO2 (s), CH3CN), ammonia (50 mL) was condensed into the flask. Once complete, lithium metal (0.07 g, 10 mmol, small pieces) was carefully added over 10 min. After stirring an additional 1 h, the reaction mixture was carefully quenched with NH4Cl (s) until the solution became clear. The bath was removed and the ammonia was allowed to evaporate over night. The resulting residue was diluted with ethyl acetate and washed successively with 0.5N HCl and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. The crude product was dissolved in 50% methanol in toluene (50 mL, 0.1 M) and treated with TMSCHN2 (2.0 M in hexanes) until the pale yellow color persisted. With TLC indicating the reaction complete, the excess TMSCHN2 was quenched with acetic acid until the solution became clear. The solution was concentrated, diluted with ethyl acetate and washed successively with saturated aqueous NaHCO3 and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. Purification by MPLC (1-60% ethyl acetate in heptane over 4 CV) gave (S)-methyl 2-(tert-butoxycarbonylamino)-2-ethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate as colorless oil (0.283 g, 71%). Rf 0.88 (30% ethyl acetate in heptane); ESI-LCMS m/z calcd for C20H38BNO6: 399.3. found 400.3 (M+1)+.
Reaction SMILES: [C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13](O)=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CSC>C1COCC1>[C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[CH2:13][OH:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CSC
Product: O=C(OCc1ccccc1)N1CCC[C@H]1CO
Temperature: 0 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
A 21.56 g (86.55 mmol) sample of the compound from step 24a above was dissolved in 200 mL of THF, and the solution was cooled to 0° C. BH3 -dimethyl sulfide (86.5 mL, 2N) was added dropwise under a nitrogen atmosphere. The reaction was stirred at room temperature for 16 hr, then cooled to 0° C. and quenched by careful addition of 10% acetic acid in methanol. The mixture was reduced in volume on a rotary evaporator, and the concentrate was dissolved in ethyl acetate, which was washed successively with 1N HCl, water and sodium bicarbonate solution, The organic extract was dried over Na2SO4 and concentrated to afford the title product, 19,94 g (98% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[C:4]=1[C:5]([NH:7][C:8]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]1)=[O:6].[CH2:32](N(C(C)C)C(C)C)[CH3:33].ICC>ClCCl>[CH2:32]([N:10]1[CH2:11][CH2:12][CH2:13][C:8]([NH:7][C:5](=[O:6])[C:4]2[C:20]([C:28]([F:31])([F:29])[F:30])=[CH:21][C:22]([C:24]([F:25])([F:26])[F:27])=[CH:23][C:3]=2[O:2][CH3:1])([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:9]1)[CH3:33]
Reactant: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)NC1(c2ccccc2)CCCNC1
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCI
Product: CCN1CCCC(NC(=O)c2c(OC)cc(C(F)(F)F)cc2C(F)(F)F)(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 58 %

Procedure:
To a solution of 25.mg (0.056 mmol) rac-2-methoxy-N-(3-phenyl-piperidin-3-yl)-4,6-bis-trifluoromethyl-benzamide in 0.25 ml dichloromethane were added 19.7 ul (0.112 mmol) N-ethyldiisopropylamine and finally 6.0 ul (0.0728 mmol) iodoethane. The solution was stirred at room temperature for 20 hours. The solvent was removed in vacuo. The crude product was purified on silica gel (Eluent: Heptane/ethyl acetate 0 to 100%) to provide 15 mg (58%) of the title compound as a colorless oil. MS (m/e): 475.2 (M+H).
Reaction SMILES: [C:1]([OH:12])(=O)[CH2:2][CH:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])[CH3:4].[NH2:13][C:14]1[C:23]2[N:24]=[C:25]([CH2:30][CH2:31][CH2:32][CH3:33])[N:26]([CH2:27][CH2:28][NH2:29])[C:22]=2[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1>>[NH2:13][C:14]1[C:23]2[N:24]=[C:25]([CH2:30][CH2:31][CH2:32][CH3:33])[N:26]([CH2:27][CH2:28][NH:29][C:1](=[O:12])[CH2:2][CH:3]([CH3:4])[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])[C:22]=2[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: CC(C)=CCCC(C)CC(=O)O
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCN
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCNC(=O)CC(C)CCC=C(C)C
Yield: 67.4 %

Procedure:
Using the general method of Example 97 citronellic acid (0.3 g, 1.7 mmole) was reacted with 2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine (0.5 g, 1.7 mmol) to provide 0.5 g of N1-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-3,7-dimethyl-6-octenamide as a white whispy solid, m.p. 163-164° C. Analysis: Calculated for C25H36N6O: % C, 68.77; % H, 8.31; % N, 19.25; Found: % C, 68.84; % H, 8.14; % N, 19.58. HRMS (EI) calcd for C25H36N6O (M+) 436.2950 found 436.2952.
Reaction SMILES: [C:1]([C:9]1[C:10](=[O:20])[N:11]([CH3:19])[C:12](=[O:18])[N:13]([CH3:17])[C:14]=1[CH2:15]Br)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][C:22]1[CH:27]=[C:26]([Cl:28])[C:25]([N+:29]([O-:31])=[O:30])=[CH:24][C:23]=1[OH:32]>C(O)C>[Cl:28][C:26]1[C:25]([N+:29]([O-:31])=[O:30])=[CH:24][C:23]([OH:32])=[C:22]([N:21]2[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:9]3[C:14]([N:13]([CH3:17])[C:12](=[O:18])[N:11]([CH3:19])[C:10]3=[O:20])=[CH:15]2)[CH:27]=1
Reactant: Cn1c(CBr)c(C(=O)c2ccccc2)c(=O)n(C)c1=O
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1O
Solvent: CCO
Product: Cn1c(=O)c2c(-c3ccccc3)n(-c3cc(Cl)c([N+](=O)[O-])cc3O)cc2n(C)c1=O
Yield: 42.2 %

Procedure:
In a 10 mL round bottom flask was placed 4a (200 mg, 595 mmol) (see Example 2 for synthesis of 4a), 2-amino-4-chloro-5-nitrophenol (236 mg, 1.25 mmol), and ethanol (5 mL). The reaction was stirred at reflux for 5 h, then cooled and placed in a freezer. After several hours yellow crystals formed, which were filtered and rinsed with cold ethanol to give 5f (225 mg, 89%). 1H NMR (600 MHz, DMSO-d6) δ 11.33 (s, 1H), 7.79 (s, 1H), 7.44 (s, 1H), 7.30 (s, 5H), 7.10 (s, 1H), 3.33 (s, 3H), 3.20 (s, 3H). 13C NMR (151 MHz, DMSO-d6) δ 158.98, 152.39, 150.82, 147.31, 134.14, 131.79, 130.50, 130.32, 129.23, 128.96, 128.33, 127.48, 113.90, 112.93, 105.91, 102.66, 31.55, 27.51. MS (ES+) (m/z): [M+1]+ calculated for C20H16ClN4O5, 427.08. found 427.12.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[C:7]2[C:3]=1[CH:4](O)[N:5](C(C)(C1C=CC=CC=1)C)[C:6]2=[O:12].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>[N+](C)([O-])=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:12]
Reactant: CC(C)(c1ccccc1)N1C(=O)c2c(I)ccc(F)c2C1O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: C[N+](=O)[O-]
Product: O=C1NCc2c(F)ccc(I)c21
Yield: 74 %

Procedure:
In a similar manner to Step 4 of Example 16, 4-fluoro-3-hydroxy-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (1.17 g, 2.86 mmol) was dissolved in nitromethane (46 mL), and the solution was treated with trifluoroacetic acid (2.20 mL, 28.6 mmol) and triethylsilane (0.914 mL, 5.72 mmol), followed by purification by flash column chromatography (chloroform/methanol=100/0, 85/15) to obtain 4-fluoro-7-iodoisoindolinone (586 mg, yield 74%).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.Br[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O.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>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([C:4]2[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=2)[CH:13]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Brc1cccnc1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(-c2cccnc2)cc1
Yield: 88.6 %

Procedure:
To a mixture of 4-tolylboronic acid (38 g, 0.28 mol), 3-bromopyridine (44 g, 0.28 mol), Na2CO3 (200 g) in toluene (500 ml) and water (500 ml) was added Pd(PPh3)4 (16 g, 0.014 mol), and refluxed for 16 h. The reaction mixture was cooled, and the separated organic layer was washed with water and brine, and dried. The solvent was removed to give 4-(3-pyridyl)toluene (42 g, 90%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:4]=1[C:5](Cl)=[O:6].C[O:15][P:16]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]2[CH:26]=[CH:27][CH:28]=[CH:29][C:18]=2[O:17]1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:4]=1[C:5]([P:16]1(=[O:15])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]2[CH:26]=[CH:27][CH:28]=[CH:29][C:18]=2[O:17]1)=[O:6]
Reactant: COP1Oc2ccccc2-c2ccccc21
Reactant: COc1cccc(OC)c1C(=O)Cl
Solvent: Cc1ccccc1
Product: COc1cccc(OC)c1C(=O)P1(=O)Oc2ccccc2-c2ccccc21
Temperature: 125 °C

Procedure:
60.1 g (0.3 mol) of 2,6-dimethoxybenzoyl chloride were warmed to 85° C. under a nitrogen atmosphere. 69 g (0.3 mol) of 6-methoxy-(6H)-dibenz[c,e][1,2]oxaphosphorin were added dropwise while stirring. The temperature was then slowly increased to 125° C. When the reaction was complete and after cooling, 150 ml of toluene were added. After crystallization, 99 g (87% of theory) of the abovementioned compound of melting point 96° to 98° C. were obtained.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([C:13]3([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:20][C:21]1[O:25][C:24]([C:26]2[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=2)=[N:23][N:22]=1>>[CH3:19][C:13]1([C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:28]4[CH:29]=[CH:30][CH:31]=[C:26]([C:24]5[O:25][C:21]([CH3:20])=[N:22][N:23]=5)[CH:27]=4)[N:3]=3)[NH:8][CH:9]=2)=[O:12])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Cc1nnc(-c2cccc(B(O)O)c2)o1
Reactant: CC1(C(=O)c2c[nH]c3ncc(Br)nc23)CCCCC1
Product: Cc1nnc(-c2cccc(-c3cnc4[nH]cc(C(=O)C5(C)CCCCC5)c4n3)c2)o1

Procedure:
(1-Methyl-cyclohexyl)-{2-[3-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenyl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-methanone was prepared starting from (2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-(1-methyl-cyclohexyl)-methanone and 3-(5-Methyl-1,3,4-oxadiazol-2-yl)phenylboronic acid following general procedures as described in these Examples. MP 234-236° C., M+H=402.
Reaction SMILES: [CH2:1]([NH:11][C:12]([C@@H:14]1[CH2:16][C@H:15]1[C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:24]([OH:32])(=[O:31])[C:25]([CH2:27][C:28](O)=[O:29])=[CH2:26]>>[CH2:1]([NH:11][C:12]([C@@H:14]1[CH2:16][C@H:15]1[C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:26][CH:25]([C:24]([OH:32])=[O:31])[CH2:27][C:28]2=[O:29])=[CH:19][CH:18]=1)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCNC(=O)[C@@H]1C[C@H]1c1ccc(N)cc1
Reactant: C=C(CC(=O)O)C(=O)O
Product: CCCCCCCCCCNC(=O)[C@@H]1C[C@H]1c1ccc(N2CC(C(=O)O)CC2=O)cc1

Procedure:
The title compound was prepared from trans-N-decyl-2-(4-aminophenyl)cyclopropanecarboxamide and itaconic acid, substantially according to the procedure of Example 10. It was recrystallized twice from ethanol to give a 47% yield of material having a melting point of 214°-215° C. The infrared spectrum (KBr disc) showed absorptions at 3280, 3125, 1680 and 1625 cm-1.
Reaction SMILES: [I:1]I.[OH-].[K+].[N+:5]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][N:12]=[CH:11]2)([O-:7])=[O:6]>CN(C=O)C>[I:1][C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[C:8]([N+:5]([O-:7])=[O:6])[CH:9]=2)[NH:13][N:12]=1
Reactant: II
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2[nH]nc(I)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Iodine (1.6 g, 6.4 mmol) and KOH (0.67 g, 12 mmol) were successfully added into a solution of 5-nitro-1H-indazole (520 mg, 3.2 mmol) in DMF. The reaction mixture was stirred at room temperature for overnight and then 10% Na2S2O5 was poured into the mixture. The titled compound (0.84 g, 91%) was filtered off as a yellow solid. MS (ESI) m/z=290 [M+H]+. 1H NMR (400 MHz, d6-DMSO) δ 14.15(s, 1H), 8.36(d, J=2 Hz, 1H), 8.26 (dd, J=2 and 9 Hz, 1H), 7.78 (d, J=9 Hz, 1H)
Reaction SMILES: [ClH:1].[C:2]1([C:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:9][C:10]2[CH:18]=[CH:17][C:13]([CH:14]([NH2:16])[CH3:15])=[CH:12][CH:11]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C[CH:27]([NH2:42])[C:28]1C=[CH:32][C:31](CCC2C=CC=CC=2)=[CH:30][CH:29]=1>>[ClH:1].[C:19]1([C:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][C:10]2[CH:18]=[CH:17][C:13]([CH:14]([N:16]=[C:27]3[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH:42]3)[CH3:15])=[CH:12][CH:11]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(N)c1ccc(C=C(c2ccccc2)c2ccccc2)cc1
Reactant: CC(N)c1ccc(CCc2ccccc2)cc1
Agent: Cl
Product: CC(N=C1CCCCCN1)c1ccc(C=C(c2ccccc2)c2ccccc2)cc1

Procedure:
Following essentially the same procedure described in Example 7 above and substituting p-(2,2-diphenylvinyl)-α-methylbenzylamine hydrochloride for the α-methyl-p-phenethylbenzylamine hydrochloride above, results in the formation of 2-[p-(2,2-diphenylvinyl)-α-methylbenzylimino]hexahydroazepine hydrochloride having a M.P. of 219°-21° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH3:22])[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)[CH:10]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:22][N:7]1[C:6]([CH2:4][OH:3])=[CH:10][C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]([F:19])([F:20])[F:21])=[CH:15][CH:16]=2)=[N:8]1
Reactant: CCOC(=O)c1cc(-c2ccc(OC(F)(F)F)cc2)nn1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cn1nc(-c2ccc(OC(F)(F)F)cc2)cc1CO

Procedure:
In analogy to the procedure described for example 1 a], 2-methyl-5-(4-trifluoromethoxy-phenyl)-2H-pyrazole-3-carboxylic acid ethyl ester was reduced with lithium aluminium hydride to give [2-methyl-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-yl]-methanol as white crystals.
Reaction SMILES: C(OC([NH:8][NH:9][C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]([CH2:19][CH3:20])[CH:13]=1)=[O:11])=O)(C)(C)C.Cl>O1CCOCC1>[CH2:19]([C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([CH3:18])[N:15]=1)[C:10]([NH:9][NH2:8])=[O:11])[CH3:20]
Reactant: CCc1cc(C(=O)NNC(=O)OC(C)(C)C)cc(C)n1
Agent: Cl
Solvent: C1COCCO1
Product: CCc1cc(C(=O)NN)cc(C)n1

Procedure:
A solution of crude N′-(2-ethyl-6-methyl-pyridine-4-carbonyl)-hydrazinecarboxylic acid tert-butyl ester in dioxane (10 mL) is treated with 4M HCl in dioxane (4 mL) for 6 h. The mixture is evaporated, the residue taken up in MeOH and the 2-ethyl-6-methyl-isonicotinic acid hydrazide hydrochloride is precipitated from Et2O as white foam; 1H NMR (CD3OD): δ 8.16 (s, 1H), 8.14 (s, 1H), 3.15 (q, J=7.6 Hz, 2H), 2.87 (s, 3H), 1.46 (t, J=7.6 Hz, 3H).
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:16])[CH2:6][C:7]([CH3:15])([O:9][O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:8])=[O:3].[CH3:17][NH:18][CH3:19]>C(OCC)C>[CH3:17][N:18]([CH3:19])[C:2](=[O:3])[O:4][CH:5]([CH3:16])[CH2:6][C:7]([CH3:15])([O:9][O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:8]
Reactant: CNC
Reactant: CC(CC(C)(C)OOC(C)(C)C)OC(=O)Cl
Solvent: CCOCC
Product: CC(CC(C)(C)OOC(C)(C)C)OC(=O)N(C)C
Reaction time: 2 h

Procedure:
To a solution of (97%) 1,3-dimethyl-3(t-butylperoxy)butyl chloroformate 5.2 g. (0.02 mole) in diethyl ether, cooled to 0°±1° C. was added a solution of dimethylamine, 1.8 g. (0.04 mole) in diethyl ether over a period of 10 minutes. After the addition was complete the mixture was allowed to stir for two hours while the reaction temperature was allowed to rise to 20°±1° C. The reaction mixture was then filtered to remove the amine hydrochloride and the organic phase washed with 10% aqueous Tartaric acid solution and water to neutrality.
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][CH2:8][C@H:9]([N:13]([C:20](=[O:35])[C@@H:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[C:26]([Cl:34])[CH:25]=1)[CH3:22])[CH2:14][CH:15](OC)OC)[CH2:10][O:11][CH3:12])(C)(C)C.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>>[Cl:34][C:26]1[CH:25]=[C:24]([N:23]2[CH2:15][CH2:14][N:13]([C@H:9]([CH2:10][O:11][CH3:12])[CH2:8][CH2:7][C:6]([OH:5])=[O:36])[C:20](=[O:35])[C@@H:21]2[CH3:22])[CH:29]=[CH:28][C:27]=1[C:30]([F:31])([F:32])[F:33]
Reactant: COC[C@H](CCC(=O)OC(C)(C)C)N(CC(OC)OC)C(=O)[C@H](C)Nc1ccc(C(F)(F)F)c(Cl)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC[C@H](CCC(=O)O)N1CCN(c2ccc(C(F)(F)F)c(Cl)c2)[C@@H](C)C1=O
Yield: 36 %

Procedure:
In analogy to intermediate 44C, (S)-4-[[(S)-2-(3-chloro-4-trifluoromethyl-phenylamino)-propionyl]-(2,2-dimethoxy-ethyl)-amino]-5-methoxy-pentanoic acid tert-butyl ester was cyclized with trifluoroacetic acid/triethylsilane to give the titled compound in 36% yield as brown oil. MS: 421.2 (MH+, 1Cl).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][N:6]([CH3:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:14][N:15]([CH3:35])[C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[C:31]3[C:26](=[CH:27][C:28]([N:32]([CH3:34])[CH3:33])=[CH:29][CH:30]=3)[C:24](=[O:25])[O:23]2)=[CH:18][CH:17]=1>[Cl-].[Zn+2].[Cl-]>[CH3:5][N:6]([CH3:13])[C:7]1[CH:12]=[CH:11][C:10]([CH:22]([C:31]2[CH:30]=[CH:29][C:28]([N:32]([CH3:33])[CH3:34])=[CH:27][C:26]=2[C:24]([OH:25])=[O:23])[C:19]2[CH:18]=[CH:17][C:16]([N:15]([CH3:14])[CH3:35])=[CH:21][CH:20]=2)=[CH:9][CH:8]=1
Reactant: CN(C)c1ccc(C2OC(=O)c3cc(N(C)C)ccc32)cc1
Reactant: CN(C)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Zn+2]
Product: CN(C)c1ccc(C(c2ccc(N(C)C)cc2)c2ccc(N(C)C)cc2C(=O)O)cc1

Procedure:
Proceeding in a manner similar to that described in part A above, but replacing the anhydrous zinc chloride with 9.3 g of anhydrous aluminum chloride, 70.0 ml of N,N-dimethylaniline and 14.9 g of 3-(4-dimethylaminophenyl)-6-dimethylaminophthalide, prepared as described in Example 1, part A above were interacted to obtain 16.1 g of 2-[4,4'-bis(dimethylamino)-benzhydryl]-5-dimethylaminobenzoic acid, a light blue powder which melted at 209°-213° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[C:26](=[O:28])=[O:27]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]2[C:17]([C:26]([OH:28])=[O:27])=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C=O
Reactant: CC(C)(C)OC(=O)NCCOc1noc2ccccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCOc1noc2cccc(C(=O)O)c12
Temperature: -70 °C

Procedure:
To a solution of 3-(2-(N-t-butoxycarbonylamino)ethoxy)-1,2-benzisoxazole (0.55 g) in tetrahydrofuran (30 ml) was added butyl lithium (3.0 ml, 1.6 M hexane solution) dropwise with stirring at -70° C. under nitrogen atmosphere, and the mixture was then stirred at the same temperature for 15 minutes. Gaseous carbon dioxide was introduced to the reaction mixture over 10 minutes and the temperature was raised to 0° C. The reaction mixture was poured into ice water (40 ml) and washed with diethylether (twice each with 40 ml). The aqueous layer was separated, after pH was adjusted to 4 with potassium dihydrogen phosphate, then extracted with ethyl acetate (twice each with 40 ml). The combined extracts were dried over anhydous magnesium sulphate, filtered and the solvent was evaporated under reduced pressure, to give 3-(2-(N-t-butoxycarbonylamino)ethoxy)-4-carboxy-1,2-benzisoxazole and 3-(2-(N-t-butoxycarbonylamino)ethoxy)-7-carboxyl-1,2-benzisoxazole as a colorless oily mixture (0.48 g).