Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[N:11][C:12]([C:15]([O:17]C)=[O:16])=[CH:13][CH:14]=2)=[N:7][CH:8]=1)#[N:2].O.[Li+].[OH-]>O1CCCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[N:11][C:12]([C:15]([OH:17])=[O:16])=[CH:13][CH:14]=2)=[N:7][CH:8]=1)#[N:2]
Reactant: COC(=O)c1ccc(-c2ccc(C#N)cn2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(-c2ccc(C(=O)O)nc2)nc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 250 ml flask was added methyl 5-cyano-2,3′-bipyridine-6′-carboxylate (950 mg, 3.57 mmol), water (9.5 ml), tetrahydrofuran (38.4 ml) and LiOH (86 mg, 3.57 mmol). The mixture was stirred for 30 min, diluted with tetrahydrofuran (200 ml) and cooled to 0° C. (ice water batch). After an additional 30 min, the resulting suspension was filtered, washed with THF and dried under reduced pressure to afford the desired product as a light brown powder. LCMS (m/z): 226.1 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:10]2[CH2:11][C:12]3[C:17]([CH:9]12)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)(Cl)Cl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[CH2:18]([O:25][C:26]1[CH:27]=[CH:28][C:29]([O:32][C@@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C@@H:10]2[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:30][CH:31]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1C2Cc3ccccc3C21
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N[C@H]1Cc2ccccc2[C@H]1Oc1ccc(OCc2ccccc2)cc1
Yield: 38.6 %

Procedure:
The title compound was prepared in a similar manner to Preparation 18 from (±) N-tert-butoxycarbonyl-1,2-iminoindane (5 g, 21.6 mmol), 4-benzyloxyphenol (4.3 g, 21.6 mmol), pyridinium p-toluenesulfonate (100 mg) and chloroform (150 ml). After a reaction time of 3 h, the reaction was diluted with chloroform (100 ml) then washed sequentially with water and brine. After drying over sodium sulfate, volatiles were removed in vacuo and the residue subjected to column chromatography on silica gel eluting with 10% diethyl ether in hexanes to afford a light brown solid which was recrystallised to afford the title compound (3.6 g) as a white solid. (from diethyl etherhexanes).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:11]=[C:12]([OH:17])[CH:13]=[CH:14][C:15]=1[F:16].S(=O)(=O)(O)O.CCCCCCC>C(O)(=O)C>[Cl:9][C:10]1[C:15]([F:16])=[CH:14][C:13]([I:1])=[C:12]([OH:17])[CH:11]=1
Reactant: Oc1ccc(F)c(Cl)c1
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CCCCCCC
Product: Oc1cc(Cl)c(F)cc1I
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.2 %

Procedure:
N-iodosuccinimide (4.61 g, 20.5 mmol), was suspended in glacial acetic acid (20 ml). To this suspension was added 3-chloro-4-fluorophenol (3.0 g, 20.0 mmol) and then concentrated sulphuric acid (0.36 ml, 6.14 mmol) was added dropwise over 5 minutes. The resulting brown/orange suspension was stirred at room temperature for 18 hours. The mixture was concentrated in vacuo and the residue was partitioned between water and dichloromethane, the dichloromethane was dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give an orange/red oil. The crude product was purified by column chromatography on silica gel using 1:1 ethyl acetate:heptane to give the title compound as a pale orange/brown solid (3.50 g, 60% yield)
Reaction SMILES: C1(C([NH:20][CH:21]2[C:39](=[O:40])[N:23]3[CH:24]([C:29]4[N:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[N:32]=[N:31][N:30]=4)[C:25]([CH3:28])([CH3:27])[S:26][C@H:22]23)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.[C:42]1([CH3:52])[CH:47]=[CH:46][C:45]([S:48]([OH:51])(=[O:50])=[O:49])=[CH:44][CH:43]=1>CC(C)=O>[NH2:20][CH:21]1[C:39](=[O:40])[N:23]2[CH:24]([C:29]3[N:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[N:32]=[N:31][N:30]=3)[C:25]([CH3:28])([CH3:27])[S:26][C@H:22]12.[CH3:52][C:42]1[CH:47]=[CH:46][C:45]([S:48]([OH:51])(=[O:50])=[O:49])=[CH:44][CH:43]=1
Reactant: CCOC(=O)n1nnnc1C1N2C(=O)C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@H]2SC1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)n1nnnc1C1N2C(=O)C(N)[C@H]2SC1(C)C
Reaction time: 3 h

Procedure:
To a stirred solution of 554 mg. of 6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[ethoxycarbonyl]tetrazol-5-yl)penam in 2 ml. of acetone is added a solution of 190 mg. of p-toluenesulfonic acid monohydrate in 1 ml. of acetone. Stirring is continued for a further 3 hours, and then the acetone is removed by evaporation in vacuo. The residue is slurried in ether, filtered and dried, to give the title compound as its p-toluenesulfonate salt.
Reaction SMILES: [Br:1]Br.[CH3:3][CH:4]([CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(OCC)C>[Br:1][CH:11]([CH:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:3])[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13]
Reactant: BrBr
Reactant: CC(CC(=O)c1ccccc1)c1ccccc1
Solvent: CCOCC
Product: CC(c1ccccc1)C(Br)C(=O)c1ccccc1

Procedure:
Bromine (0.02 mol) was added dropwise to a stirred solution of 2-(α-methylbenzyl)acetophenone (0.02 mol) in dry diethyl ether (20 ml) at 5° over one hour. The ether was removed in vacuo and the residue redissolved in ether (100 ml), washed with saturated sodium bicarbonate solution (2 × 100 ml) and then water (4 × 100 ml), and dried over anhydrous sodium sulphate. Removal of the solvent gave a solid which on recrystallisation from petroleum ether (40°-60°) gave 2-bromo-3-phenylbutyrophenone, m.p. 69°-71°.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([N:17]3[CH2:22][CH:21]=[C:20](B4OC(C)(C)C(C)(C)O4)[CH2:19][CH2:18]3)=[O:16])=[CH:10][CH:9]=2)[CH2:4]1.Br[C:34]1[CH:35]=[C:36]([S:40][CH3:41])[CH:37]=[CH:38][CH:39]=1>>[CH3:32][N:2]([CH3:1])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([N:17]3[CH2:22][CH:21]=[C:20]([C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([S:40][CH3:41])[CH:35]=4)[CH2:19][CH2:18]3)=[O:16])=[CH:10][CH:9]=2)[CH2:4]1
Reactant: CN(C)C1CCN(c2ccc(NC(=O)N3CC=C(B4OC(C)(C)C(C)(C)O4)CC3)cc2)C1
Reactant: CSc1cccc(Br)c1
Product: CSc1cccc(C2=CCN(C(=O)Nc3ccc(N4CCC(N(C)C)C4)cc3)CC2)c1

Procedure:
4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide was reacted with 3-bromothioanisole by method O-a. This resulted in the product with the molecular weight of 436.62 (C25H32N4OS); MS (ESI): 437 (M+H+)
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[C:5](Cl)(=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[S:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1.Cl>ClC1C=CC=CC=1>[CH2:5]([C:15]1[S:14][CH:18]=[CH:17][CH:16]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: c1ccsc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: c1ccc(Cc2cccs2)cc1
Temperature: 0 °C

Procedure:
27.2 g of 98.5% pure aluminium trichloride (sublimed) were suspended in 130 ml of chlorobenzene and cooled to 0° C. 28.7 g of benzoyl chloride were added dropwise while stirring and cooling over the course of 30 minutes, and the mixture was then stirred for 1 hour. Likewise at 0° C., a solution of 17.3 g of thiophene in 27 ml of chlorobenzene was added dropwise over the course of 30 minutes, and the mixture was stirred for 1 hour. Remaining hydrogen chloride was driven out by heating the mixture and stirring, finally under vacuum. The remaining solution was introduced over the course of 40 minutes into a solution of 12.7 g of dimethylamineborane in 70 ml of chlorobenzene while stirring at 70° C. The mixture was then stirred for 1 hour, cooled and discharged into a mixture of 200 g of ice and 50 g of concentrated aqueous hydrochloric acid while stirring. The aqueous phase was then separated off and extracted with chlorobenzene. The remaining organic phase was extracted by shaking with water. The organic phase and the extract from the aqueous phase were then combined, the solvent was removed therefrom by distillation, and 38.7 g of crude 2-benzylthiophene of 79.7% purity were obtained by distillation. This corresponds to 88.5% of theory. Redistillation resulted in 99.7% pure 2-benzylthiophene with a boiling point of 91° to 92° C./1.4 mbar.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]3[NH:23][N:24]=[C:25]([O:26][C@@H:27]4[O:53][C@H:52]([CH2:54][O:55]C(=O)C(C)(C)C)[C@@H:44]([O:45]C(=O)C(C)(C)C)[C@H:36]([O:37]C(=O)C(C)(C)C)[C@H:28]4[O:29]C(=O)C(C)(C)C)[C:18]=23)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].C(O)(=O)C>CO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]3[NH:23][N:24]=[C:25]([O:26][C@@H:27]4[O:53][C@H:52]([CH2:54][OH:55])[C@@H:44]([OH:45])[C@H:36]([OH:37])[C@H:28]4[OH:29])[C:18]=23)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3nccc(CCc4ccc(OCc5ccccc5)cc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: OC[C@H]1O[C@@H](Oc2n[nH]c3nccc(CCc4ccc(OCc5ccccc5)cc4)c23)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 50 °C
Reaction time: 5 h
Yield: 84.8 %

Procedure:
To a solution of 4-[2-(4-benzyloxyphenyl)ethyl]-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazolo[3,4-b]pyridine (49 mg) in methanol (4 mL) was added sodium methoxide (0.056 mL), and the mixture was stirred at 50° C. for 5 hours. To the reaction mixture was added acetic acid (0.033 mL), and the resulting mixture was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1-5/1) to give 4-[2-(4-benzyloxyphenyl)ethyl]-3-(β-D-glucopyranosyloxy)-1H-pyrazolo[3,4-b]pyridine (25 mg). This material was dissolved in methanol (4 mL). To the solution was added 10% palladium-carbon powder (10 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere overnight. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (16 mg).
Reaction SMILES: [NH3:1].[CH2:2]([O:4][C:5]([C:7]1[N:8]=[CH:9][N:10]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:17][CH:18]=3)[N:13]=[C:12](Cl)[C:11]=12)=[O:6])[CH3:3]>C(Cl)(Cl)Cl.C(O)C>[CH2:2]([O:4][C:5]([C:7]1[N:8]=[CH:9][N:10]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:17][CH:18]=3)[N:13]=[C:12]([NH2:1])[C:11]=12)=[O:6])[CH3:3]
Reactant: N
Reactant: CCOC(=O)c1ncn2c1c(Cl)nc1cc(C(F)(F)F)ccc12
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCOC(=O)c1ncn2c1c(N)nc1cc(C(F)(F)F)ccc12
Yield: 57 %

Procedure:
A small stream of anhydrous ammonia was passed through a solution of 4-chloro-7-trifluoromethylimidazo[1,5-a]quinoxaline 3-carboxylic acid ethyl ester (5.4 g) in chloroform-ethanol (100 ml each) for 30 minutes. The precipitate was collected and recrystallized from DMF to give the product as an off-white crystalline solid (2.9 g, 57% yield), m.p. >300° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]([N:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>>[C:2]1([CH2:1][N:8]2[CH2:13][CH2:12][N:11]([CH:24]3[CH2:25][CH2:26][N:21]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:22][CH2:23]3)[CH2:10][CH2:9]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: c1ccc(CN2CCNCC2)cc1
Product: CC(C)(C)OC(=O)N1CCC(N2CCN(Cc3ccccc3)CC2)CC1
Yield: 60 %

Procedure:
In operating analogously to preparation XXVIII, starting with N-benzylpiperazine and N-Boc-4-piperidinone, the product sought after is obtained as a colourless oil (yield=60%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7]1[N:8]=[CH:9][N:10]([C:12]2[N:13]=[N:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24](=[NH:27])[NH:25][CH3:26])=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)[CH:11]=1)=[O:4].[CH2:28](N)[CH2:29][CH2:30]C>>[CH2:26]([NH:25][C:24]([C:21]1[CH:22]=[CH:23][C:18]([C:15]2[N:14]=[N:13][C:12]([N:10]3[CH:11]=[C:7]([CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])[N:8]=[CH:9]3)=[CH:17][CH:16]=2)=[CH:19][CH:20]=1)=[NH:27])[CH2:28][CH2:29][CH3:30]
Reactant: CNC(=N)c1ccc(-c2ccc(-n3cnc(CCC(=O)OC)c3)nn2)cc1
Reactant: CCCCN
Product: CCCCNC(=N)c1ccc(-c2ccc(-n3cnc(CCC(=O)OC)c3)nn2)cc1

Procedure:
Prepared analogously to (97) with n-butylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([O:13][CH2:14][C:15]3([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH3:12])[CH:10]=1)[NH:7][N:6]=[CH:5]2.C=O.[C:29]([BH3-])#N.[Na+]>C(#N)C.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([O:13][CH2:14][C:15]3([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:16][CH2:17][N:18]([CH3:29])[CH2:19][CH2:20]3)[CH3:12])[CH:10]=1)[NH:7][N:6]=[CH:5]2
Reactant: [BH3-]C#N
Reactant: CC(OCC1(c2ccccc2)CCNCC1)c1cc(Cl)cc2cn[nH]c12
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CC(OCC1(c2ccccc2)CCN(C)CC1)c1cc(Cl)cc2cn[nH]c12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(±)-5-Chloro-7-(1-((4-phenylpiperidin-4-yl)methoxy)ethyl)-1H-indazole (40 mg, 0.11 mmol) and formaldehyde (37 wt. % solution in water, 156 μL) were combined in acetonitrile (2 mL) and cooled to 0° C. The reaction was treated with sodium cyanoborohydride (34 mg, 0.54 mmol) and a few drops of acetic acid. The reaction was stirred at 0° C. for 30 min and at room temperature for 1 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol. The solvents were evaporated to afford 30 mg (72%). 1H-NMR (CDCl3, 500 MHz) δ 7.89 (s, 1H), 7.55 (d, J=1.8 Hz, 1H), 7.39-7.42 (m, 2H), 7.34-7.37 (m, 1H), 7.27 (m, 2H), 6.97 (d, J=1.5 Hz, 1H), 4.52 (q, J=6.7 Hz, 1H), 3.35 (d, J=9.2 Hz, 1H), 3.23 (d, J=8.9 Hz, 1H), 3.11-3.26 (m, 2H), 2.45-2.53 (m, 2H), 2.49 (s, 3H), 2.38-2.40 (m, 2H), 2.25-2.30 (m, 2H), 1.46 (d, J=6.7 Hz, 3H); 13C-NMR (126 MHz, CDCl3) δ ppm 135.5, 133.6, 129.3, 127.5, 127.4, 126.9, 126.0, 124.9, 124.4, 119.1, 78.2, 51.5, 51.4, 44.4, 40.5, 30.2, 22.0. Mass spec.: 384.16 (MH)+.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].[Li+].CC([N-]C(C)C)C.[CH2:17]([O:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>C1COCC1>[CH2:7]([O:6][C:1](=[O:5])[C:2]([CH3:4])([CH3:3])[CH:29]([C:28]1[CH:27]=[CH:26][C:25]([O:24][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:32][CH:31]=1)[OH:30])[CH3:8]
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)C(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)C(O)c1ccc(OCc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 67.3 %

Procedure:
Ethyl isobutyrate (2.5 mL, 18.42 mmol) was dissolved in THF (8 mL), and the solution was cooled to −78° C. LDA (9.2 mL, 18.42 mmol) was added thereto, and the mixture was stirred at the corresponding temperature for 2 hours. After 4-benzyloxy-benzaldehyde (1.7 g, 8.01 mmol) obtained in Step A was added thereto at −78° C., the mixture was heated to room temperature, and then stirred for 2 days. The reactant was added with water, and then extracted with EtOAc. The organic layer was concentrated under reduced pressure. The residue was purified by column chromatography (eluent, EtOAc/Hex=1/5) to obtain the title compound (1.77 g, 67%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][N:4]=[C:3]1[CH2:13][CH2:14][CH2:15][CH:16]=[CH2:17].B1C2CCCC1CCC2.[OH-:27].[Na+].OO>C1COCC1>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:5][N:4]=[C:3]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:27]
Reactant: C=CCCCc1nnc(-c2ccccc2)n1C
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(CCCCCO)nnc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-methyl-3-(4-penten-1-yl)-5-phenyl-4H-1,2,4-triazole (200 mg, 0.88 mmol) in THF (1 mL) was added 9-BBN (0.5M in THF, 1.76 mmol) and the solution was refluxed for 2 h. Two more portions of 9-BBN (0.88 mmol) were added, each after 1 h. The reaction mixture was cooled down at 0 C and was added NaOH (3M, 21Mmol) in one portion followed by dropwise addition of H2O2 (33% in water, 21Mmol). The mixture was stirred for another 2 h at r.t.
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][NH:14][CH3:15])[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:22][CH2:23][C:24]1[CH:32]=[CH:31][C:27]([CH2:28][CH2:29]Br)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][N:14]([CH2:29][CH2:28][C:27]2[CH:31]=[CH:32][C:24]([CH2:23][OH:22])=[CH:25][CH:26]=2)[CH3:15])[C:8]([NH2:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CNCCCC(C(N)=O)(c1ccccc1)c1ccccc1
Reactant: OCc1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCCC(C(N)=O)(c1ccccc1)c1ccccc1)CCc1ccc(CO)cc1

Procedure:
A mixture containing 2,2-diphenyl-5-methylaminopentanamide (0.24 g-see Preparation 3), 4-hydroxymethylphenethyl bromide (0.19 g), anhydrous potassium carbonate (0.5 g) and acetonitrile (20 ml) was heated under reflux for 4 hours. The mixture was partitioned between dichloromethane (50 ml) and 5% aqueous sodium carbonate (30 ml), the layers separated and the aqueous layer extracted with dichloromethane (3×30 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a gum which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 5%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a foam, yield 0.14 g.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[CH3:13][NH:14][CH3:15]>>[CH3:13][N:14]([CH3:15])[C:7](=[O:8])[C:6]1[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: CNC
Product: CN(C)C(=O)c1cccc([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 87 %

Procedure:
3-Nitrobenzoyl chloride (1.03 g, 5.5 mmol) was treated with dimethylamine (40% aqueous solution) (5 ml). The reaction mixture was stirred under Argon for 2 hours, and then extracted with dichloromethane (70 ml). The organic extract was dried (Na2SO4) and concentrated in vacuo to afford the title compound as a pale yellow solid (0.94 g, 87%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH:12](OCC)(OCC)OCC>>[CH3:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:6][CH:12]=[N:1]2)=[CH:7][CH:8]=1
Reactant: Cc1ccc(C(N)=O)c(N)c1
Reactant: CCOC(OCC)OCC
Product: Cc1ccc2c(=O)[nH]cnc2c1
Temperature: 110 °C

Procedure:
A suspension of 2-amino-4-methylbenzamide (1.2 g, 8.0 mmol) in CH(OEt)3 (10 mL) was heated in a sealed tube at 110° C. for 4 h. Then the reaction was quenched with aq. NaHCO3 solution at rt and the precipitate obtained was filtered and dried. The solid mass was purified by column chromatography to afford 1.1 g of the title product. 1H NMR (300 MHz, DMSO-d6): δ 12.14 (br s, 1H), 8.05 (s, 1H), 8.00 (d, J=7.8 Hz, 1H), 7.47 (s, 1H), 7.34 (d, J=7.8 Hz, 1H), 2.45 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]=[C:35]=[O:36]>O1CCCC1>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[NH:34][C:35](=[O:36])[O:18][C:15]1[CH:16]=[C:17]2[C:12]([CH2:11][CH2:10][CH2:9][N:8]2[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:13][CH:14]=1
Reactant: Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Reactant: COc1ccccc1N=C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccccc1NC(=O)Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Temperature: 35 °C

Procedure:
A mixture of 1-benzyl-1,2,3,4-tetrahydroquinolin-7-ol (500 mg, 2.09 mM) and triethylamine in dry tetrahydrofuran (THF, 5 ml) was stirred for half an hour under nitrogen atmosphere at room temperature (35° C.). To the stirred reaction mixture, 2-methoxyphenyl isocyanate (417 mg/ml, 3.14 mM) was added at once and then the reaction mixture was further stirred for 72 hours under N2 atmosphere at RT. The reaction mixture was concentrated under vacuum and then was added distilled water (15 mL) followed by the extraction with ether (3×15 mL). The ether layer was dried over sodium sulphate and concentrated under vacuum to afford the crude product, which was finally chromatographed using chloroform-hexane (1:9) to give 8i as solid. Yield: 0.623 g, 76.85%.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[N:37](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:36]=[N:35][N:34]=3)=[CH:23][CH:22]=2)[C:7](=[O:19])[N:8]([CH:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH3:12])[N:9]=1)[CH2:2][CH2:3][CH3:4]>C(O)(=O)C>[CH2:1]([C:5]1[N:6]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[NH:37][N:36]=[N:35][N:34]=3)=[CH:25][CH:26]=2)[C:7](=[O:19])[N:8]([CH:10]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:11][CH3:12])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(C(CC)c2ccccc2)c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Product: CCCCc1nn(C(CC)c2ccccc2)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Deprotection of 5-n-butyl-2,4-dihydro-2-(1-phenylpropyl)-4-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]-3H-1,2,4-triazol-3-one in 67% aqueous acetic acid was accomplished by the procedure of Example 3, Step B. After work-up, the residue was flash chromatographed over silica gel (15 mL for 0.065 mmole, gradient elution using 2-20% MeOH/CH2Cl2, mass spectrum (FAB) 494 (M+1)+, mp 72°-75° C.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][SH:4].[C:10](C1NC=CN=1)(C1NC=CN=1)=[O:11]>C1COCC1>[O:11]=[C:10]1[NH:1][C@H:2]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][S:4]1
Reactant: CCOC(=O)[C@H](N)CS
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1CSC(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 169.2 %

Procedure:
To a solution of 3-1 (8.5 g, 22.6 mmol) in 200 mL THF was added of carbonyl diimidazole (12.5 g) and the solution was stirred overnight at room temperature. The solution was concentrated in vacuo, 200 mL of 5% Na2CO3 was added and the solution stirred for one hour whereupon 6M HCl was added until the pH of the solution remained at 2. The solution was extracted with EtOAc, the organic phases were then combined, dried over MgSO4, filtered and concentrated in vacuo. The compound was purified by flash chromatography using 40% EtOAc/hexanes to yield 6.7 g of 3-2 as a colorless oil. 1H NMR (400 MHz, acetone-d6): δ 7.5 (br s, 1H), 4.5 (dd, 1H), 4.2 (q, 2H), 3.8 (dd, 1H), 3.6 (dd, 1H), 1.2 (t, 3H).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8]1>>[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:13][CH:14]=2)[CH2:9][CH2:8]1
Reactant: O=S(=O)(O)Cl
Reactant: CN1CCc2ccccc21
Product: CN1CCc2cc(S(=O)(=O)Cl)ccc21
Temperature: 25 °C

Procedure:
A solution of chlorosulfonic acid at 0° C. (5 mL, 75 mmol) was treated portionwise with 1-methylindoline (CAS No. [824-21-5], 1.96 g, 14.7 mmol), warmed to room temperature, heated at 75° C. for 40 minutes, cooled, and poured onto ice to provide a solid. The solid was collected by suction filtration, washed with water, and dried to provide 927 mg of the desired product.