Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][NH:6][C:7]1[N:12]=[CH:11][CH:10]=[CH:9][N:8]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:29][C:30]1[CH:31]=[C:32]([S:38](Cl)(=[O:40])=[O:39])[C:33]([F:37])=[CH:34][C:35]=1[F:36]>O1CCCC1>[Cl:29][C:30]1[C:35]([F:36])=[CH:34][C:33]([F:37])=[C:32]([S:38]([N:6]([CH2:5][C:4]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:3]=2[O:2][CH3:1])[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][N:12]=2)(=[O:40])=[O:39])[CH:31]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)c(F)cc1F
Reactant: COc1ccc(CNc2ncccn2)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ncccn2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Temperature: 0 °C
Reaction time: 24 h
Yield: 19 %

Procedure:
A solution of (2,4-dimethoxybenzyl)-pyrimidin-2-yl-amine (Preparation 12, 736 mg, 3 mmol) in anhydrous tetrahydrofuran (20 mL) was cooled to −78° C. before the addition of a 1M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (3.30 mL, 3.30 mmol). The reaction was allowed to warm to 0° C. for 30 minutes before cooling again to −78° C. The resulting solution was added to a solution of 3-chloro-4,6-difluorobenzenesulfonyl chloride (890 mg, 3.6 mmol) in tetrahydrofuran (10 mL) at −78° C. After 30 minutes at this temperature the reaction was warmed to room temperature and stirred for 24 hours. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution and extracted into ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (50-100% dichloromethane in heptane gradient elution) to afford the title compound as a white solid (260 mg, 19%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:14]2[NH:15][C:16]3[C:21]([CH:22]=2)=[CH:20][C:19]([F:23])=[CH:18][CH:17]=3)=[N:9][C:10]([Cl:13])=[CH:11][CH:12]=1)(=O)=O.[CH2:26]([Sn](CCCC)(CCCC)C=C)[CH2:27]CC.[Li+].[Cl-]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:13][C:10]1[N:9]=[C:8]([C:14]2[NH:15][C:16]3[C:21]([CH:22]=2)=[CH:20][C:19]([F:23])=[CH:18][CH:17]=3)[C:7]([CH:26]=[CH2:27])=[CH:12][CH:11]=1
Reactant: O=S(=O)(Oc1ccc(Cl)nc1-c1cc2cc(F)ccc2[nH]1)C(F)(F)F
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=Cc1ccc(Cl)nc1-c1cc2cc(F)ccc2[nH]1
Temperature: 50 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
To a mixture of 6-chloro-2-(5-fluoro-1H-indol-2-yl)pyridin-3-yl trifluoromethanesulfonate (200 mg, 0.51 mmol), tributyl(vinyl)stannane (170 mg, 0.54 mmol) and anhydrous LiCl (70 mg, 1.65 mmol) in DMF (2 mL), Pd(PPh3)2Cl2 (30 mg, 0.04 mmol) was added under N2 protection. The reaction mixture was stirred at 50° C. for 1 h. Then it was filtered and concentrated in vacuo, the residue was purified by column chromatography (PE: EA=20:1) to give the product of 2-(6-chloro-3-vinylpyridin-2-yl)-5-fluoro-1H-indole (100 mg, yield: 72.4%). 1H-NMR (CDCl3, 400 MHz) δ 11.67 (br s, 1H), 8.05 (d, J=8.4 Hz, 1H), 7.45˜7.55 (m, 2H), 7.38 (d, J=10.0 Hz, 1H), 7.15 (dd, J=17.2, 11.2 Hz, 1H), 7.00˜7.06 (m, 1H), 6.84 (d, J=2.0 Hz, 1H), 5.93 (d, J=17.2 Hz, 1H), 5.59 (d, J=11.2 Hz, 1H). MS (M+H)+: 273/275.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][O:14][C:15]3[CH:39]=[CH:38][C:18]([CH2:19][N:20]4[CH:24]=[C:23]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[C:22]([CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[CH:21]4)=[CH:17][CH:16]=3)=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][O:14][C:15]3[CH:39]=[CH:38][C:18]([CH2:19][N:20]4[CH:24]=[C:23]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[C:22]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[CH:21]4)=[CH:17][CH:16]=3)=[N:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3ccc(-c4ccccc4)cn3)cc2)cc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CCc1cn(Cc2ccc(OCc3ccc(-c4ccccc4)cn3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
After a mixture of ethyl 3-[1-[4-(5-phenyl-2-pyridylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionate (1020 mg), 1N aqueous sodium hydroxide solution (4 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, 1 N hydrochloric acid (4 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[1-[4-(5-phenyl-2-pyridylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionic acid (930 mg, yield: 97%). This was recrystallized from acetone-hexane. Melting point: 169–170° C.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[NH:3]1.Br[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)=[O:32].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[F:39][C:36]1[CH:37]=[CH:38][C:33]([C:31](=[O:32])[CH2:30][N:3]2[C:2](=[O:1])[C:7]([CH2:8][C:9]3[CH:10]=[CH:11][C:12]([C:15]4[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:13][CH:14]=3)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]3[N:26]=[CH:27][N:28]=[C:4]23)=[CH:34][CH:35]=1
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2ncnn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(=O)c2ccc(F)cc2)c2ncnn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
A mixture of 4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (1 g), 2-bromo-1-(4-fluorophenyl)ethanone (0.65 mL), potassium carbonate (0.75 g) and N,N-dimethylformamide (15 mL) was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.78 g, 57%).
Reaction SMILES: [C:1]1([N:7]2[C:15]3[CH2:14][CH2:13][CH2:12][C:11](=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:10]=3[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CCO.[Pd]>[C:1]1([N:7]2[C:15]3[CH2:14][CH2:13][CH2:12][CH:11]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:10]=3[CH:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C=C1CCCc2c1cnn2-c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC1CCCc2c1cnn2-c1ccccc1
Reaction time: 18 h
Yield: 99.3 %

Procedure:
Pd—C (150 mg, 10%) is added to a solution of a mixture of E/Z isomers of ethyl (1,5,6,7-tetrahydro-1-phenyl-4H-indazol-4-ylidene)acetate (1.6 g, 5.67 mmol) in 50 mL of EtOH, and the resulting solution is stirred under nitrogen atmosphere (50 psi) in a Parr hydrogenator for 18 hours. The reaction mixture is purged with nitrogen, filtered through Celite and the solvent is evaporated under reduced pressure, to obtain ethyl 2-(4,5,6,7-tetrahydro-1-phenyl-1H-indazol-4-yl)acetate (1.60 g, 5.63 mmol, 99%, oil).
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[CH:13][C:14]#[N:15])=[CH:4][CH:3]=1.N.C(O)C>C(O)C.[Co]>[NH2:15][CH2:14][CH:13]=[C:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([NH2:1])[C:10]=2[O:11][CH3:12])[CH2:6][CH2:7]1
Reactant: COc1c(N)ccc2c1C(=CC#N)CC2
Agent: [Co]
Agent: N
Solvent: CCO
Product: COc1c(N)ccc2c1C(=CCN)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
To a solution of (6-amino-7-methoxy-2,3-dihydro-1H-inden-1-ylidene)acetonitrile (15.2 mg, 0.076 mmol) in ethanol (0.5 mL) were added Raney cobalt (150 mg) and 2N ammonia/ethanol solution (0.5 mL), and the mixture was stirred at room temperature for 2 hr under a hydrogen atmosphere. The catalyst was filtered off using celite, and the filtrate was concentrated under reduced pressure to give the title compound (15.3 mg, yield 99%).
Reaction SMILES: [Cl:1][CH:2]([CH2:5][Cl:6])[CH2:3][OH:4].[CH2:7]([O:9][CH2:10]OCC)[CH3:8]>O.C1(C)C(S(O)(=O)=O)=CC=CC=1>[CH2:7]([O:9][CH2:10][O:4][CH2:3][CH:2]([CH2:5][Cl:6])[Cl:1])[CH3:8]
Reactant: OCC(Cl)CCl
Reactant: CCOCOCC
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Product: CCOCOCC(Cl)CCl
Reaction time: 5 h
Yield: 91.9 %

Procedure:
A mixture of 516 g (4.0 mol) 2,3-dichloro-1-propanol, 2.0 g toluenesulfonic acid hydrate, and 1500 ml (12.0 mol) diethoxymethane (DEM) was stirred at reflux while distilling out a mixture of ethanol and DEM. After 5 hr, 200ml had distilled and 250 ml fresh DEM was added. The reaction was shut off overnight and resumed the next day for 5 hr, reaching a final internal temperature of 99° C. Base wash and distillation yielded 688 g of C2H5OCH2OCH2CHClCH2Cl, bp 60-70° C./0.3 mm. Of this amount, 210.7 g was fluorinated in PMM as in Example 1 and the product analyzed by 19F NMR as containing C2F5OCF2OCF2CFClCF2Cl in 69% yield, accompanied by the 1,3-dichloride isomer in about 5% yield. Distillation gave the main cut bp 110° C., 96% pure by glc.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[C:7]1[C:12]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[Cl:21])=[C:11]([Cl:22])[C:10]([NH:23][CH2:24][CH:25]([OH:27])[CH3:26])=[N:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1>C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[C:1]([O:5][C:6](=[O:28])[C:7]1[C:12]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[Cl:21])=[C:11]([Cl:22])[C:10]([NH:23][CH2:24][C:25](=[O:27])[CH3:26])=[N:9][CH:8]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(O)CNc1ncc(C(=O)OC(C)(C)C)c(Nc2ccc(Br)cc2Cl)c1Cl
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: CC#N
Solvent: CN1CCOCC1
Product: CC(=O)CNc1ncc(C(=O)OC(C)(C)C)c(Nc2ccc(Br)cc2Cl)c1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 30.8 %

Procedure:
To a solution of 4-(4-bromo-2-chlorophenylamino)-5-chloro-6-(2-hydroxypropylamino)-nicotinic acid tert-butyl ester (0.28 g, 0.57 mmol) in acetonitrile (1.1 mL) was added 4 Å molecular sieves and N-methylmorpholine (0.10 g, 0.85 mmol). The mixture was cooled to 0° C. and tetrapropylammonium perruthenate (0.030 g, 0.085 mmol) was added. After stirring for one hour, the reaction was filtered through a plug of silica gel, washing with EtOAc. The filtrate was concentrated. Purification by flash column chromatography (20:1 hexanes/ethyl acetate) provided the desired product as a white solid (86 mg, 31%). MS APCI (+) m/z 490, 492 (M+, Cl, Br pattern) detected.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([F:23])([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([F:23])([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(F)(C#Cc2ccc(F)cc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(F)(CCc2ccc(F)cc2)CC1
Yield: 43 %

Procedure:
A solution of 1-tert-butoxycarbonyl-4-fluoro-4-[2-(4-fluorophenyl)ethynyl]piperidine in methanol (20 ml) and glacial acid (1 ml) was hydrogenated over 10% Pd-C (0.5 g) at 50 psi for 5 hours. The catalyst was removed by filtration and the solvents removed under vacuum. The residue was dissolved in diethyl ether (20 ml) and washed with saturated aqueous sodium hydrogen carbonate (2×15 ml), dried (MgSO4) and concentrated to give the title product (430 mg, 43%) which was used in the next step without further purification; δH (360 MHz, CDCl3) 1.46 (9H, s), 1.48-1.67 (2H, m), 1.82-1.93 (4H, m), 2.68-2.73 (2H, m), 3.05-3.20 (2H, m), 3.90-3.99 (2H, m), 6.94-6.99 (2H, m), 7.11-7.15 (2H, m): m/z (ES) 326 (M+ +1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[CH3:20])(=[O:12])=[O:11])[S:7][CH:8]=1.[CH3:21][N:22]1[CH:26]=[C:25]([S:27](Cl)(=[O:29])=[O:28])[N:24]=[CH:23]1>C(Cl)Cl>[Cl:19][C:15]1[C:14]([CH3:20])=[C:13]([S:10]([NH:9][C:6]2[S:7][CH:8]=[C:4]([CH2:3][CH2:2][NH:1][S:27]([C:25]3[N:24]=[CH:23][N:22]([CH3:21])[CH:26]=3)(=[O:29])=[O:28])[N:5]=2)(=[O:11])=[O:12])[CH:18]=[CH:17][CH:16]=1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(CCN)cs1
Solvent: ClCCl
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(CCNS(=O)(=O)c2cn(C)cn2)cs1
Temperature: 25 °C
Yield: 56.4 %

Procedure:
A suspension of EXAMPLE 200A (200 mg, 0.60 mmol), 1-methylimidazole-4-sulphonyl chloride (109 mg, 0.60 mmol), TEA (61 mg, 0.60 mmol) in DCM (10 mL) was refluxed for 1 h. The reaction mixture was allowed to cool to room temperature and the solid was filtered off giving 161 mg (58%) of pure title compound: MS (Ionspray, [M+H]+) m/z 476; Anal. Calcd. (found) for C16H18ClN5O4S3: C, 40.4 (40.2) %; H, 3.8 (3.8)%; N, 14.7 (14.6)%.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:11])=[CH:8][C:9]=1[OH:10])=[O:3].[OH-].[Na+].[Cl:14][O-].[Na+].Cl>O>[Cl:14][C:8]1[C:9]([OH:10])=[C:4]([C:2](=[O:3])[CH3:1])[CH:5]=[CH:6][C:7]=1[OH:11]
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: [O-]Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)c1ccc(O)c(Cl)c1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 65 %

Procedure:
A solution of 2,4,-dihydroxyacetophenone (6 g, 39.4 mmol), aqueous 1M sodium hydroxide (41.4 mL, 41.4 mmol) and water (200 mL) is stirred at room temperature. An aqueous 1.6M solution of sodium hypochlorite (32 mL) is added over a 1 hr period. The resulting dark brown solution is stirred 18 hr at room temperature. The reaction mixture is adjusted to a pH of 2-3 with concentrated aqueous hydrochloric acid. The resulting suspension is filtered and washed with water (4×100 mL). The filtered solid was dried under vacuum at 45° C. for 2.5 days to give the title compound (4.8 g, 65%) as a brown solid. LCMS 1 187 m+.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.Cl.Cl[CH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1.[OH-].[Na+].C1COCC1>CN(C=O)C.O>[N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]=[CH:25][C:16]=1[CH2:15][O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][C:9]#[N:10])=[CH:11][CH:12]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: N#CCCOc1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: N#CCCOc1ccc(OCc2ccc3ccccc3n2)cc1

Procedure:
A mixture of 2.93 g (0.018 mol) 3-(4-hydroxyphenoxy)propionitrile, 3.2 g (0.18 mol) 2-chlormethylquinoline hydrochloride and 18 ml (2N, NaOH) in 25 ml DMF and 25 ml THF is heated over a steam bath for a period of 24 hours. The reaction mixture is poured into water and extracted with ether. The ether extract is washed with water, dried over MgSO4 and concentrated to dryness under reduced pressure. The residue is passed through a silica gel column using hexane/ethyl acetate (3:1) as eluent to obtain the desired product which is used directly in the next step.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][OH:4].[H][H]>[Pd]>[CH:8]1([CH2:7][CH2:6][CH2:5][CH:2]([CH3:1])[CH2:3][OH:4])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: [H][H]
Reactant: CC(CO)CCCc1ccccc1
Agent: [Pd]
Product: CC(CO)CCCC1CCCCC1
Reaction time: 30 h
Yield: 94.3 %

Procedure:
1200 g of 2-Methyl-5-phenyl-pentanol (Rosaphen™, supplier: Symrise) combined with 22 g Pd on activated carbon (Pd content: 5 wt. %) were hydrogenated at a hydrogen pressure of 50 bar and at a temperature of 120° C. After 30 hours the reaction was finished. The catalyst was removed and the product distilled. 1170 g (content: 99.6%) of 5-cyclohexyl-2-methyl-pentanol were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12].[CH2:15](O)[CH3:16]>>[CH2:15]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([S:11](=[O:13])(=[O:14])[NH2:12])[CH:4]=1)[CH3:16]
Reactant: NS(=O)(=O)c1cc(C(=O)O)ccc1Cl
Reactant: CCO
Product: CCOC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Yield: 99 %

Procedure:
To a suspension of 4-chloro-3-sulfamoyl-benzoic acid (50 g, 212 mmol) in 500 mL ethanol is bubbled HCl gas for 10 minutes. The resulting suspension is then heated at reflux for 16 h, cooled and concentrated in vacuo. The resulting residue is recrystallized from isopronanol to yield 55.9 g (99%) of the title compound as an off-white solid.
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([OH:17])[CH:10]=[CH:11][CH:12]=3)[C:7](=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.Cl>[OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([OH:17])[CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2cccc(O)c2C(=O)c2cccc(O)c21
Agent: Cl
Solvent: CC(=O)O
Product: O=C1c2cccc(O)c2Cc2cccc(O)c21
Temperature: 5 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
To a suspension of 1,5-dihydroxyanthraquinone (10 g, 41.6 mmole) and stannous chloride (45 g, 237 mmole) in glacial acetic acid (150 ml), conc. hydrochloric acid (90 ml) was added at 16°-20° C. The resulting mixture was stirred for 4 hours under reflux. After standing at room temperature overnight, the reaction mixture was cooled to 5° C. A precipitate was filtered, washed with H2O and dried to afford 8.0 g of 1,5-dihydroxyanthrone as dark brown needles having a m.p. of 231°-233° C.
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:9])=[O:8])=[N:4][CH:3]=1.[Cl-].[Li+].C[Sn](C)C.C[Sn](C)C.Cl[C:26]1[N:35]=[C:34]([NH:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=2)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][C:32]=2[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[N:27]=1>O1CCOCC1>[C:11]([NH:10][S:7]([C:5]1[S:6][C:2]([C:26]2[N:35]=[C:34]([NH:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=3)[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][C:32]=3[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[N:27]=2)=[CH:3][N:4]=1)(=[O:9])=[O:8])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)NS(=O)(=O)c1ncc(Br)s1
Reactant: Clc1nc(NCc2ccccn2)c2c(-c3ccccc3)cccc2n1
Agent: C[Sn](C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: CC(C)(C)NS(=O)(=O)c1ncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)cccc3n2)s1
Temperature: 90 °C
Yield: 4.5 %

Procedure:
To a stirring suspension of 5-bromo-N-tert-butylthiazole-2-sulfonamide (0.50 g, 1.67 mmol) in 1,4-dioxane (10 mL) was added lithium chloride (0.210 g, 5.03 mmol), followed by hexamethylditin (0.820 g, 2.50 mmol). After degassing with nitrogen, Pd(TPP)4 (0.19 g, 0.16 mmol) was added. The resultant suspension was stirred for over night at RT. 2-Chloro-5-phenyl-N-(pyridin-2-ylmethyl)quinazolin-4-amine (0.46 g, 1.33 mmol) was dissolved in 1,4-dioxane (3 mL) and then added to the reaction mixture. Upon completion of addition, the reaction mixture was heated at 90° C. for 24 h. After this time, the solvent was evaporated, water was added and the mixture was extracted with DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated. The resulting residue was purified by recrystallization with ethyl acetate and further purified by preparative HPLC (method H) to provide N-tert-butyl-5-(5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl)thiazole-2-sulfonamide (32 mg, 4.2%) as a yellow solid. LCMS Method V: Rt 2.47 min; [M+1]=531.2; HPLC Method A1: purity 97.3%, retention time=10.89 min.
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12]C)=[C:10]([O:14]C)[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][C:7]2=[O:16]>ClCCl.CO>[Cl:1][C:2]1[C:11]([OH:12])=[C:10]([OH:14])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][C:7]2=[O:16]
Reactant: COc1cc2c(c(Cl)c1OC)CCNC2=O
Solvent: CO
Solvent: ClCCl
Product: O=C1NCCc2c1cc(O)c(O)c2Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To the solution of 5-chloro-6,7-dimethoxy-3,4-dihydroisoquinolin-1(2H)-one (700 mg, 2.90 mmol) in dichloromethane (DCM) (2 mL) at −78° C. was added borontribromide (0.821 mL, 8.69 mmol). Mixture was allowed to warm up to room temperature and stirred at room temperature for 1 hour. Mixture was diluted with methanol and stripped several times to give 5-chloro-6,7-dihydroxy-3,4-dihydroisoquinolin-1(2H)-one (619 mg, 2.90 mmol, 100% yield) LCMS (M+H)+: 214.0
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[O:9][CH:8]([C:15]([F:18])([F:17])[F:16])[C:7]([C:19]([OH:21])=[O:20])=[CH:6]2)[CH3:2].[OH-].[Na+:23]>C(O)C>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[O:9][CH:8]([C:15]([F:16])([F:17])[F:18])[C:7]([C:19]([O-:21])=[O:20])=[CH:6]2)[CH3:2].[Na+:23]
Reactant: CCc1cc2c(cc1OC)OC(C(F)(F)F)C(C(=O)O)=C2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1cc2c(cc1OC)OC(C(F)(F)F)C(C(=O)[O-])=C2
Temperature: 25 °C

Procedure:
To the solution of 0.785 g (2.51 mm) of 6-ethyl-7-methoxy-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid in 20 mL of ethanol was added 24.9 mL of 0.1008 N aqueous solution of sodium hydroxide. The resulting solution was stirred at room temperature for half an hour. The volatiles were removed. The residue was dissolved in 20 mL of water. The resulting solution was frozen and lyophilized to give a light yellow solid. LC-MS (ES−) 301 (M−H, 100). HRMS (ES−) m/z calcd for (M−1; C14H12F3O4) 301.0790, found 301.0810.
Reaction SMILES: [Br:1][C:2]1[C:7]2[S:8][C:9]([NH2:11])=[N:10][C:6]=2[CH:5]=[C:4]([Br:12])[N:3]=1.[CH2:13]([N:15]=[C:16]=[O:17])[CH3:14]>O1CCOCC1.O>[Br:1][C:2]1[C:7]2[S:8][C:9]([NH:11][C:16]([NH:15][CH2:13][CH3:14])=[O:17])=[N:10][C:6]=2[CH:5]=[C:4]([Br:12])[N:3]=1
Reactant: Nc1nc2cc(Br)nc(Br)c2s1
Reactant: CCN=C=O
Solvent: C1COCCO1
Solvent: O
Product: CCNC(=O)Nc1nc2cc(Br)nc(Br)c2s1
Temperature: 80 °C
Yield: 82.8 %

Procedure:
To a solution of 4,6-dibromothiazolo[5,4-c]pyridin-2-amine (1.47 g, 56.74% as per LCMS, 2.70 mmol) in 1,4-dioxane (75 mL) was added ethylisocyanate (1.30 mL, 16.25 mmol) and the resulting reaction mixture was heated to 80° C. for 16 h. The solvent was distilled off under reduced pressure and the residue was then co-distilled with hexane (twice). The solid thus obtained was stirred in hot water at 80° C. for 30 min then filtered. The solid material was purified over silica gel (100-200 M, 30-40% EtOAc-hexane) to obtain the desired product as an off-white solid (0.85 g, 82%).
Reaction SMILES: [C:1]1([C@H:7]([CH2:12][CH3:13])[CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14](Cl)(=[O:18])[C:15](Cl)=O>C(Cl)Cl>[CH2:12]([C@H:7]([C:8]1[C:9](=[O:11])[O:10][C:8]2[CH2:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:15]=2[C:14]=1[OH:18])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:13]
Reactant: CC[C@H](CC(=O)O)c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC[C@@H](c1ccccc1)c1c(O)c2c(oc1=O)CCCCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3[R]-Phenylvaleric acid of formula VV-3 (400 mg) is added to methylene chloride (5 mL) followed by oxalyl chloride (0.21 mL). That mixture is heated at reflux for 3 hours. The methylene chloride is removed and 1,3,5-trimethylbenzene (10 mL) is added. The solution of the acid chloride is then heated to reflux temperatures and the title product of Preparation 87 [VV-2](210 mg) and triethylamine (210 mg) (both in 1.5 mL of 1,3,5-trimethylbenzene) are added dropwise. After complete addition the reaction is heated for an addition 3 hours. The reaction is cooled to room temperature and the solid removed by filtration. The filtrate is evaporated and the resulting residue is diluted with methanol (35 mL) and 0.5N NaOH (4 mL) and that mixture stirred at room temperature overnight. The methanol is removed and water (35 mL) added. The aqueous is extracted with ether/hexane (2×35 mL) and the aqueous is acidified with 1.6N HCl at 0° C. to pH 3. That aqueous is extracted with ethyl acetate, dried and solvent removed in vacuo to yield 318.5 mg of the title product VV-5. Chromatography over silica gel (EtOAc/methylene chloride 1:8) affords 249.2 mg of the title product.