Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[C:5]([N+:10]([O-])=O)[C:3]=1[NH2:4].C(O)C.[H][H]>O.[Ni]>[Cl:1][C:2]1[C:3]([NH2:4])=[C:5]([NH2:10])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: [H][H]
Reactant: Nc1c([N+](=O)[O-])ccc(Cl)c1Cl
Agent: [Ni]
Solvent: CCO
Solvent: O
Product: Nc1ccc(Cl)c(Cl)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
2,3-Dichloro-6-nitroaniline (20.11 g, 97.14 mmol), Raney-nickel (4.78 g of a 50% slurry in water), and ethanol (250 mL) were combined in an autoclave which was pressurized to 150 psig with hydrogen. The resulting reaction mixture was allowed to stir at RT overnight. The mixture was then filtered through a pad of celite, which was subsequently washed with several portions of methanol, and the solvents were removed by rotary evaporation to leave a dark brown solid. The solid was slurried and in hexanes and was collected on a Büchner funnel to afford 16.31 g (95%) of a brown solid. MS (EI): m/z 177.0 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7](B(O)O)[CH:8]=[CH:9][CH:10]=1)=[O:4].O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[NH2:24][C:25]1[CH:34]=[CH:33][C:32]([C:35]([C:37]2[N:45]3[C:40]([CH:41]=[CH:42][CH:43]=[CH:44]3)=[C:39](Br)[C:38]=2[CH3:47])=[O:36])=[CH:31][C:26]=1[C:27]([O:29][CH3:30])=[O:28]>COCCOC.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>[NH2:24][C:25]1[CH:34]=[CH:33][C:32]([C:35]([C:37]2[N:45]3[C:40]([CH:41]=[CH:42][CH:43]=[CH:44]3)=[C:39]([C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:10]=3)[C:38]=2[CH3:47])=[O:36])=[CH:31][C:26]=1[C:27]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)c1cc(C(=O)c2c(C)c(Br)c3ccccn23)ccc1N
Reactant: COC(=O)c1cccc(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=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1cccc(-c2c(C)c(C(=O)c3ccc(N)c(C(=O)OC)c3)n3ccccc23)c1
Temperature: 90 °C
Yield: 65.9 %

Procedure:
0.229 g (1.27 mmol) of [3-(methoxycarbonyl)phenyl]boronic acid, 0.492 g (2.12 mmol) of potassium phosphate dihydrate and 0.024 g (0.02 mmol) of tetrakis(triphenylphosphine)palladium are added, under an argon atmosphere at ambient temperature, to 0.410 g (1.06 mmol) of methyl 2-amino-5-[(1-bromo-2-methylindolizin-3-yl)carbonyl]benzoate in 8 ml of a DME/H2O (5/1) mixture. The reaction medium is heated at 90° C. for 18 hours. The reaction medium is extracted with dichloromethane, washed with a saturated aqueous solution of sodium chloride, dried over sodium sulphate, filtered, and then concentrated under reduced pressure. The solid obtained is purified by silica gel column chromatography, elution being carried out with dichloromethane. 309 mg of a yellow solid are obtained.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[O:5][C:4](=[O:14])[CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>C1COCC1>[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([C:3]2[C:4](=[O:14])[O:5][C:6]3[C:11]([C:2]=2[CH3:1])=[CH:10][CH:9]=[C:8]([C:12]#[N:13])[CH:7]=3)=[O:31])=[CH:28][CH:27]=1
Reactant: Cc1cc(=O)oc2cc(C#N)ccc12
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(C(=O)c2ccc(Cl)cc2)c(=O)oc2cc(C#N)ccc12
Reaction time: 1 h

Procedure:
To a solution of 4-methyl-2-oxo-2H-chromene-7-carbonitrile (170 mg, 0.918 mmol) in dry THF (5 mL) at −20° C. was added drop wise 1.0 M LiHMDS solution in THF (1 mL). After 30 minutes 4-chloro-benzoyl chloride (160 μL) was added slowly and the reaction mixture was stirred for 1 hour. The reaction mixture was then quenched with saturated aqueous ammonium chloride (10 mL) and extracted with ethyl acetate (50 mL). The organic layer was separated and dried over sodium sulfate, then concentrated and purified on silica gel eluted with 30% ethyl acetate in hexanes to yield the title compounds as a white foam and a white solid, respectively.
Reaction SMILES: [ClH:1].Cl.Cl.[NH2:4][CH2:5][CH2:6][CH2:7][NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:30])[CH:15]([NH:17][C:18](=[O:29])[CH:19]=[CH:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]([NH2:28])=[NH:27])[OH:16].Cl.[CH3:32]O>CO>[ClH:1].[ClH:1].[ClH:1].[NH2:4][CH2:5][CH2:6][CH2:7][NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:30])[CH:15]([NH:17][C:18](=[O:29])[CH:19]=[CH:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]([NH2:28])=[NH:27])[O:16][CH3:32]
Reactant: CO
Reactant: N=C(N)NCCCCC=CC(=O)NC(O)C(=O)NCCCCNCCCN
Agent: Cl
Product: COC(NC(=O)C=CCCCCNC(=N)N)C(=O)NCCCCNCCCN
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
To a solution of 50.3 mg (0.10 mmole) of N-[4-(3-aminopropyl)aminobutyl]-2-(7-guanidino-2-heptenamido)-2-hydroxyethanamide trihydrochloride in 1 ml of anhydrous methanol was added 0.1 ml of 2N hydrogen chloride-methanol. The mixture was stirred overnight at room temperature and the reaction mixture was concentrated under reduced pressure. The residue was purified in a manner similar to that in Example 7 using CM-Sephadex® C-25 (Na-type) and Sephadex® LH-20 to obtain 37.2 mg (72.4% yield) of N-[4-(3-aminopropyl)aminobutyl]-2-(7-guanidino-2-heptenamido)-2-methoxyethanamide trihydrochloride.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.Cl[CH2:12][C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:14].N12CCCN=C1CCCCC2>C1C=CC=CC=1>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:12][C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:14])=[O:7])=[CH:4][CH:3]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CCN(CC)C(=O)CCl
Solvent: c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCN(CC)C(=O)COC(=O)c1ccc(N)cc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of 4-aminobenzoic acid (1.37 g. 0.01 mole), 2-chloro-N,N-diethylacetamide 2.0 ml, 0.015 mole) and 1.8-diazabicyclo[5.4.0]-undec-7-ene (1.52 g, 0.01 mole) in benzene (20 ml) was stirred at 80° C. for 4 h and then evaporated in vacuo. The residue was taken up in ethyl acetate. After washing with 5% sodium bicarbonate and water the ethyl acetate extract was dried and evaporated in vacuo leaving crude title compound. Recrystallization from ethanol-water gave 1.5 g (60%). Mp 135°-136° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([O:13][CH3:14])=[O:12])[CH:2]=1>[Pt](=O)=O>[CH3:14][O:13][C:11]([C:3]1[CH:2]=[N:1][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=1)=[O:12]
Reactant: COC(=O)c1cnc2ccccc2c1
Agent: O=[Pt]=O
Product: COC(=O)c1cnc2c(c1)CCCC2
Temperature: 60 °C
Reaction time: 5 h

Procedure:
Representative procedure for small scale hydrogenation reactions. To a 2 or 3-neck, 100 ml round bottom flask containing a stir bar was added methyl quinoline-3-carboxylate (170 mg, 0.908 mol) and platinum (IV) oxide (10.3 mg, 5 mol %). The flask was equipped with two outlets sealed with rubber septa and containing Teflon stopcocks. Trifluoroacetic acid (3.0 mL), which was purged with argon gas to remove oxygen, was added via a plastic syringe into the reaction flask under an atmosphere of nitrogen. The stirred reaction mixture was flushed and the flask filled with hydrogen gas via a needle from a balloon through one of the septa-sealed outlets. The Teflon stopcocks were closed and the reaction mixture was warmed to 60° C. and stirred for 5 hours. The progress of the reaction was monitored by GC and TLC. The reaction mixture was cooled to room temperature and aqueous saturated sodium bicarbonate solution was added until the mixture was neutral. The mixture was then extracted with CH2Cl2 (3×30 mL), dried (MgSO4), and the solvent was removed in vacuo. The crude material thus obtained was separated by flash chromatography (silica gel, 10% EtOAc in hexanes). The title compound was obtained as a yellowish liquid (121 mg, 70%) which displayed: 1H NMR (CDCl3, 300 MHz): δ 1.80–2.00 (m, 4H), 2.79–2.85 (m, 2H), 2.90–3.00 (m, 2H), 3.91 (s, 3H), 7.95 (s, 1H), 8.93 (s, 1H); 13C NMR (CDCl3): δ 22.8, 23.1, 28.9, 30.0, 33.1, 52.5, 123.7, 132.5, 138.0, 148.2, 162.6, 166.5; MS m/z: 192 (M+H+). 1,2,3,4-Tetrahydroquinoline-3-carboxylic acid methyl ester also was isolated (19 mg, 11%).
Reaction SMILES: Cl.BrCCC[NH2:6].C(N(CC)CC)C.Cl[S:15]([C:18]1[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=1[C:20](OC)=[O:21])(=[O:17])=[O:16]>ClCCl>[OH:16][S:15]1([OH:17])[C:18]2[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=2[C:20](=[O:21])[NH:6]1
Reactant: NCCCBr
Reactant: COC(=O)c1ccccc1S(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1NS(O)(O)c2ccccc21
Temperature: 25 °C
Reaction time: 66 h
Yield: 33.3 %

Procedure:
3-Bromopropylamine hydrochloride (2.189 g, 10 mmol) was suspended in 15 ml of dry dichloromethane, and to the suspension were added triethylamine (7 ml, 50 mmol) and methyl 2(chlorosulfonyl)benzoate (2.738 g, 10.5 mmol). The mixture was stirred at room temperature for 66 hours, poured into ice water, extracted with dichloromethane, washed with water, dried over sodium sulfate, and concentrated. The residue was purified by flash chromatography on silica gel to give 617 mg of 1,1-Dihydroxy-3-oxo-3H-benzo[d]isothiazole (20%). The isothiazole was etherified with Deg. B-Bh-Ester by the NaH/DMF method described above, and the compound was subjected to deprotection to remove the Bh group by the TFA/Anisole method described above, providing 309 mg of the desired compound 120 (97%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:31])=[C:6]([C@@:8]2([NH:19][C:20]([NH:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[S:21])[C@H:13]([CH2:14]O)[CH2:12][C@H:11]([CH:16]3[CH2:18][CH2:17]3)[O:10][CH2:9]2)[CH:7]=1.[N:32]1C=CC=C[CH:33]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>ClCCl>[C:33]([C:2]1[CH:3]=[CH:4][C:5]([F:31])=[C:6]([C@:8]23[CH2:9][O:10][C@@H:11]([CH:16]4[CH2:18][CH2:17]4)[CH2:12][C@H:13]2[CH2:14][S:21][C:20]([NH:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:19]3)[CH:7]=1)#[N:32]
Reactant: c1ccncc1
Reactant: O=C(NC(=S)N[C@@]1(c2cc(Br)ccc2F)CO[C@@H](C2CC2)C[C@H]1CO)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(F)c([C@]23CO[C@@H](C4CC4)C[C@H]2CSC(NC(=O)c2ccccc2)=N3)c1
Temperature: 0 °C

Procedure:
A solution of N-{[(3S,4R,6R)-3-(5-bromo-2-fluorophenyl)-6-cyclopropyl-4-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]carbamothioyl}benzamide (C57) (127 mg, 0.28 mmol) and pyridine (81 μL, 1.01 mmol) in dichloromethane (12 mL) was cooled to −50° C. Trifluoromethanesulfonic anhydride (94 μL, 0.56 mmol) was added drop-wise to the solution and the mixture was gradually warmed to 0° C. over 90 minutes. The reaction mixture was diluted with dichloromethane (20 mL), washed with water (2×30 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) afforded the product as a solid. Yield: 83 mg, 68%. LCMS m/z 436.2 [M+H+].
Reaction SMILES: [CH3:1][C:2]([C:7]1[S:11][C:10]([NH:12][C:13](=[O:30])[CH:14]([NH:18][C:19](=[O:29])[CH2:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=2)[CH2:15][CH2:16][CH3:17])=[N:9][N:8]=1)([CH3:6])[CH2:3][CH:4]=[CH2:5].ClC1C=CC=C(C(OO)=[O:39])C=1>C(Cl)Cl>[CH3:1][C:2]([C:7]1[S:11][C:10]([NH:12][C:13](=[O:30])[CH:14]([NH:18][C:19](=[O:29])[CH2:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=2)[CH2:15][CH2:16][CH3:17])=[N:9][N:8]=1)([CH3:6])[CH2:3][CH:4]1[CH2:5][O:39]1
Reactant: C=CCC(C)(C)c1nnc(NC(=O)C(CCC)NC(=O)Cc2cc(F)cc(F)c2)s1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1nnc(C(C)(C)CC2CO2)s1
Reaction time: 4 h

Procedure:
A mixture of 2-[2-(3,5-difluoro-phenyl)-acetylamino]-pentanoic acid [5-(1,1-dimethyl-but-3-enyl)-[1,3,4]thiadiazol-2-yl]-amide (196 mg, 0.45 mmol) and ˜60% pure m-chloroperbenzoic acid (109 mg, 0.45 mmol) in methylene chloride was stirred for 4 hr. The mixture was quenched with water, saturated Na2S2O3 and extracted with methylene chloride. The organic layer was washed with brine, separated, dried, and concentrated to give 114 mg of crude material with a mixture of desired title compound and undesired N-oxide and recovered starting material. The crude material was purified by HPLC and the title compound was isolated, LC-MS, RT=2.3 min, M=1=453.5.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:8][C:7](=O)[N:6]2[N:10]=[CH:11][CH:12]=[C:5]2[N:4]=1.P(Cl)(Cl)([Cl:15])=O.C(N(CC)CC)C>C(#N)C>[Cl:15][C:7]1[N:6]2[N:10]=[CH:11][CH:12]=[C:5]2[N:4]=[C:3]([S:2][CH3:1])[N:8]=1
Reactant: CSc1nc2ccnn2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CSc1nc(Cl)n2nccc2n1
Yield: 71 %

Procedure:
In a round bottom flask equipped with a magnetic stirbar, 2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-4(3H)-one (1.0 eq, 10.43 g, 57.24 mmol) was suspended in acetonitrile (100 ml). Phosphorus oxychloride (4.0 eq, 21 ml, 229.4 mmol) and triethylamine (1.05 eq, 8.4 ml, 60.27 mmol) were added and the mixture stirred at reflux for 3.5 hours, at which time LCMS indicated completion of the reaction. The mixture was cooled down and slowly poured into crushed ice (final total volume of about 600 ml). The solid was filtered, washed with water and dried in a vacuum oven to afford 4-chloro-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine as a tan solid (8.15 g, 71% yield). LCMS (ES): >97% pure, m/z 201 [M+H]+.
Reaction SMILES: [OH:1][C@@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[C:29]1([C:35]2[CH:40]=[CH:39][C:38](O)=[CH:37][CH:36]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[C:29]1([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:34]=[CH:33][C:32]([O:1][C@H:2]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=3)[CH2:7][CH2:6]2)=[CH:31][CH:30]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](Oc3ccc(-c4ccccc4)cc3)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 41.1 %

Procedure:
A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137 mmol), 4-phenylphenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (3.00 mg, 41.2% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 7.48 (m, 2H), 7.40–7.30 (m, 8H), 7.30–7.25 (m, 4H), 6.97 (apparent d, 1H, J=7.6 Hz), 6.91 (apparent d, 2H, J=8.7 Hz), 5.34 (apparent dd, 1H, J=4.4, 8.0 Hz), 3.40 (m, 2H), 2.98 (m, 2H), 2.53 (apparent sept, partially hidden, 1H, J=8.1 Hz), 2.44 (m, 1H), 2.30–2.10 (m, 6H), 1.93 (d, 2H), 1.26 (d, 6H, J=6.9 Hz); ESMS m/e: 533.4 (M+H)+.
Reaction SMILES: C(O[C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[NH2:13])C.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.C(O)(=O)C>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([N:13]2[C:7]3[C:6](=[CH:11][C:10]([Cl:12])=[CH:9][CH:8]=3)[CH2:5][C:4]2=[O:14])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CCOC(=O)Cc1cc(Cl)ccc1N
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)Cc3cc(Cl)ccc32)CC1
Yield: 138.8 %

Procedure:
(2-Amino-5-chloro-phenyl)-acetic acid ethyl ester (3.3 g, 15.4 mmol), 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (4.6 g, 23 mmol) were set stirring in CH2Cl2 (50 mL) and sodium triacetoxyborohydride (4.9 g, 23.1 mmol) was added followed by acetic acid (3 mL). After 5 days saturated NaHCO3 was added and the organics separated. The organics were dried (MgSO4) and evaporated to give 7.5 g of a clear golden oil. The oil was purified (silica, 50% EtOAc/hexanes) to give 3.4 g (63%) of a white solid. TLC (silica, 25% EtOAc/hexanes): Rf=0.18. MS (electrospray): exact mass calculated for C18H23ClN2O3, 350.14. m/z found, 373.1 [M+Na]+. 1H NMR (400 MHz, CDCl3): 7.40-7.30 (m, 2H), 7.00 (d, J=8.4 Hz, 1H), 4.55-4.45 (m, 1H), 4.40 (m, 2H), 3.63 (s, 2H), 2.94 (m, 2H), 2.45-2.30 (m, 2H), 1.82 (m, 2H), 1.62 (s, 9H).
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[C:20]([Cl:22])[CH:21]=1>>[Cl:15][C:16]1[CH:17]=[C:18]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:19]=[C:20]([Cl:22])[CH:21]=1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Product: Nc1nnc(-c2cc(Cl)cc(Cl)c2)c(-c2ccccc2)n1
Yield: 34.4 %

Procedure:
6-(3,5-Dichlorophenyl)-5-phenyl-1,2,4-triazin-3-amine (130 mg, 34%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.30 g, 1.19 mmol) and 3,5-dichlorophenylboronic acid (0.42 g, 2.19 mmol) according to the general procedure of Example 1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:10](Cl)(=[O:12])=[O:11])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[CH2:14]([O:16][C:17](=[O:29])[CH:18]([NH2:28])[CH:19]([C:24]([F:27])([F:26])[F:25])[C:20]([F:23])([F:22])[F:21])[CH3:15].N1C=CC=CC=1>C(Cl)Cl>[CH2:14]([O:16][C:17](=[O:29])[CH:18]([NH:28][S:10]([C:4]1[CH:3]=[C:2]([F:1])[C:7]([F:8])=[C:6]([F:9])[CH:5]=1)(=[O:12])=[O:11])[CH:19]([C:20]([F:23])([F:21])[F:22])[C:24]([F:26])([F:27])[F:25])[CH3:15]
Reactant: CCOC(=O)C(N)C(C(F)(F)F)C(F)(F)F
Reactant: O=S(=O)(Cl)c1cc(F)c(F)c(F)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C(NS(=O)(=O)c1cc(F)c(F)c(F)c1)C(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Yield: 84.3 %

Procedure:
A solution of 3,4,5-trifluorobenzenesulfonyl chloride (0.348 mL, 2.50 mmol) in CH2Cl2 (5 mL) was added to a solution of 2-amino-4,4,4-trifluoro-3-trifluoromethyl-butyric acid ethyl ester (0.4 g, 1.67 mmol) prepared as described (J. Med Chem. 1981, 24, 1043-1047), and pyridine (0.27 mL, 3.34 mmol) in CH2Cl2 (5 mL) at 0° C. and allowed to warm to 25° C. for 19 h. The solution was washed with 1M HCl (1 mL), brine (1 mL), dried over Na2SO4 and concentrated. The crude solid was purified by Biotage Flash™ chromatography, eluting with EtOAc/hexanes (1:4), to give 4,4,4-trifluoro-2-(3,4,5-trifluoro-benzenesulfonylamino)-3-trifluoromethyl-butyric acid ethyl ester (0.63 g, 85%) as a white solid. Mass Spectrum (+ESI): 448 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[C:5]([OH:18])=[CH:6][C:7]2[C:8]([CH3:17])([CH3:16])[CH2:9][CH2:10][C:11]([CH3:15])([CH3:14])[C:12]=2[CH:13]=1)([CH3:3])[CH3:2].Br[C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1>>[CH:1]([C:4]1[C:5]([O:18][C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=2)=[CH:6][C:7]2[C:8]([CH3:16])([CH3:17])[CH2:9][CH2:10][C:11]([CH3:15])([CH3:14])[C:12]=2[CH:13]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(Br)cc1
Reactant: CC(C)c1cc2c(cc1O)C(C)(C)CCC2(C)C
Product: COC(=O)c1ccc(Oc2cc3c(cc2C(C)C)C(C)(C)CCC3(C)C)cc1

Procedure:
In a manner similar to Example 1(a) above, by the reaction of 2 g (8.1 mmol) of 3-isopropyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthol with 1.45 g (6.7 mmol) of methyl 4-bromo-benzoate, 840 mg (33%) of the expected methyl ester of melting point 115-6° C. were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][CH2:11][C:12](=O)[CH3:13])=[CH:5][CH:4]=1.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][NH2:25])=[CH:19][CH:18]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][N:25]2[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:19][CH:18]=1
Reactant: COc1ccc(C(=O)CCC(C)=O)cc1
Reactant: NCCc1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccc(C)n2CCc2ccc(Br)cc2)cc1
Yield: 68 %

Procedure:
A solution of 1-(4-methoxyphenyl)-1,4-pentanedione (3.20 g, 15.5 mol), 2-(4-bromophenyl)ethylamine (3.74 g, 18.7 mmol) and p-toluenesulfonic acid monohydrate (150 mg, 0.871 mmol) in toluene (100 ml) was refluxed for 20 hours with heating. The insoluble matter was filtered out and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:1) to give the object compound as an oily substance. 3.93 g (yield: 68.0%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([S:18][CH:19]([CH2:22][OH:23])[CH2:20][OH:21])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[F:25][C:26]([F:42])([F:41])[C:27]1[CH:32]=[CH:31][C:30](/[CH:33]=[CH:34]/[CH:35]=[CH:36]/[CH:37]=[CH:38]/[CH:39]=O)=[CH:29][CH:28]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([S:18][C@@H:19]1[CH2:20][O:21][C@@H:39](/[CH:38]=[CH:37]/[CH:36]=[CH:35]/[CH:34]=[CH:33]/[C:30]2[CH:29]=[CH:28][C:27]([C:26]([F:25])([F:41])[F:42])=[CH:32][CH:31]=2)[O:23][CH2:22]1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: O=C/C=C/C=C/C=C/c1ccc(C(F)(F)F)cc1
Reactant: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Product: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/C=C/c2ccc(C(F)(F)F)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 65 %

Procedure:
Reaction was carried out in the same manner as in Example 4 using (2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl)thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol and (2E,4E,6E)-7-[4-(trifluoromethyl)phenyl]-2,4,6-heptatrienal as described in Reference example 28 to obtain the title compound, a major product as an oil in a yield of 65%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][C@@H:12]2[CH2:16][O:15][C@@H:14]3[C@H:17](OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:18][O:19][C@H:13]23)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Br-:31].[Li+].O>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][C@@H:12]2[CH2:16][O:15][C@@H:14]3[C@@H:17]([Br:31])[CH2:18][O:19][C@H:13]23)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: [Br-]
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3OS(=O)(=O)c2ccc(C)cc2)cc1
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)O[C@@H]2CO[C@H]3[C@@H]2OC[C@@H]3Br)cc1
Temperature: 100 °C
Yield: 21.2 %

Procedure:
A stirred mixture of ditosylate (39) (16.9 g, 37.22 mmol) and lithium bromide (4.85 g, 55.84 mmol) in N,N-dimethylformamide (100 mL) was heated at 100° C. for 27 hours. The mixture was allowed to cool then water (150 mL) added before extracting with tert-butyl methyl ether (1×100 mL then 5×50 mL). The organic phase was dried (MgSO4), filtered and reduced in vacuo to give a colourless oil which solidified on standing. Flash chromatography over silica, eluting with ethyl acetate:heptane mixtures 0:100 to 80:20 gave bromotosylate (46) as a white solid (2.86 g, 29%). TLC (Rf=0.45 diethyl ether heptane, 1:1), analytical HPLC: Rf=16.768 min; HPLC-MS: 363.1/365.0 [M+H]+, 380.1/382.1, 749.0/751.0 [2M+Na]+; [□]D18+64.7° (c=8.5, CHCl3); δH (500 MHz, CDCl3) 2.45 (3H, s, CH3), 3.74 (1H, dd, 7.05 Hz, CH2), 3.95 (1H, dd, 6.47 Hz, CH2), 4.14-4.22 (2H, m, CH2), 4.29 (1H, d, J=3.03 Hz, CHBr), 4.68 (1H, d, J=4.03 Hz, CHCH), 4.76 (1H, t, J=4.48 Hz, CHOTs), 4.87 (1H, m, CHCH), 7.36 (2H, brd, J=7.97 Hz, aromatic CH3CCH), 7.83 (2H, brd, J=8.33 Hz, aromatic OSO2CCH). δC (125 MHz, CDCl3) 21.69 (CH3), 50.06 (CHBr), 70.26 (CH2CHOTs), 76.54 (CH2CHBr), 78.27 (CHOTs), 80.17 and 88.80 (CHCHCHOTs), 127.98 and 129.94 (aromatic CH), 133.01 (CHOSO2C quaternary), 145.28 (CH3C quaternary).