Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OP([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])(COCC)=O)C.[H-].[Na+].[Si:18]([O:25][CH2:26][CH2:27][CH2:28][CH:29]=O)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>C1COCC1>[Si:18]([O:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])([C:21]([CH3:22])([CH3:23])[CH3:24])([CH3:19])[CH3:20]
Reactant: CCOCP(=O)(CC(=O)OCC)OCC
Reactant: CC(C)(C)[Si](C)(C)OCCCC=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/CCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.1 %

Procedure:
Ethyl 2-(ethoxy(ethoxymethyl)phosphoryl)acetate (75.8 g, 0.3386 mol) was added to NaH (13.5 g, 60%) in 600 mL THF at 0° C., and the solution was warmed at RT for 1 hour, followed by the addition of 4-(tert-butyldimethylsilyloxy)butanal (5) (57.0 g, 0.2822 mol) in THF (200 mL) at 0° C., The mixture was stirred at RT for 2 hours. After removal of the solvent, the residue was dissolved in DCM, and the mixture was washed with water (3×200 mL) and brine (3×200 mL), dried over Na2SO4 and concentrated to give the desired compound of (E)-ethyl 6-(tert-butyldimethylsilyloxy)hex-2-enoate (7) (37.0 g, yield 48%) as yellow oil which was purified by column chromatography on silica gel (eluent: PE:EA=30:1). 1H NMR (300 MHz, CDCl3): δ 0.0021 (S, 6H), 0.0857 (S, 9H), 1.197 (t, 3H), 1.600 (m, 2H), 1.197 (t, 3H), 2.240 (q, 2H), 3.586 (t, 2H), 4.098 (q, 2H), 5.832 (d, J=15.6 Hz, 1H), 6.936-6.885 (m, 1H); LC-MS found 273 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[O:7][CH2:6][CH2:5][O:4]1)[CH3:2].C([Li])(C)(C)C.CN([CH:21]=[O:22])C.Cl>C1COCC1>[CH2:1]([C:3]1([C:8]2[S:9][C:10]([CH:21]=[O:22])=[CH:11][CH:12]=2)[O:4][CH2:5][CH2:6][O:7]1)[CH3:2]
Reactant: CCC1(c2cccs2)OCCO1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCC1(c2ccc(C=O)s2)OCCO1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
15 g (81.4 mmol) of 2-ethyl-2-2-thienyl-[1,3]dioxolane are dissolved in 300 mL of anhydrous THF and the mixture is then cooled to −78° C. 53 mL (89 mmol) of 1.7 M tert-butyllithium solution are then added, after which the reaction medium is stirred for 1 hour. 10 mL (120 mmol) of anhydrous DMF are then added and the medium is stirred for 1 hour. The reaction medium is treated at −78° C. with 1N hydrochloric acid solution and is then extracted with ethyl acetate and the organic phases are combined, dried and concentrated under reduced pressure. The residue obtained is purified by chromatography on a column of silica. A yellow oil is obtained (m=19 g; Y=100%).
Reaction SMILES: C(=O)([O-])OC[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:6][C:5]=1[Br:17].C[O-:21].[Na+].Cl>C(Cl)Cl>[Br:17][C:5]1[CH:6]=[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[OH:21]
Reactant: CC(C)(C)c1cc(Br)c(COC(=O)[O-])cc1[N+](=O)[O-]
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)c1cc(Br)c(O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(2-Bromo-4-tert-butyl-5-nitro-phenyl)methyl carbonate (72.9 g, 219.5 mmol) was charged to a reactor and DCM (291.6 mL) was added. The yellow reaction solution was cooled using an ice bath. Sodium methoxide (67.04 g, 69.11 mL of 5.4 M, 373.2 mmol) was added portion-wise at 2.2-6.9° C. After complete addition, the reaction was slowly warmed to ambient temperature. When complete, the reaction was cooled to 0° C. and quenched with 1M HCl (373.2 mL, 373.2 mmol). The biphasic mixture was stirred for 20 min and transferred to a seperatory funnel. The organic layer was separated and washed with water (300 mL) followed by brine (300 ml). The organic layer was concentrated and the crude product dried under high vacuum. The product was further purified using Supercritical Fluid Chromatography (SFC) separation on a Berger MultiGram III (Mettler Toledo AutoChem, Newark Del.). The method conditions were 20% methanol at 250 mL/min on a PPU column (30*150) from Princeton Chromatography, 100 bar, 35 C, 220 nm. An injection of 3.5 mL of a 55-70 mg/mL solution was injected. The data was collected using SFC ProNTo software. The purified product received from SFC purification was a methanol solvate. To remove the methanol, an azeotropic distillation was performed. The dark yellow solid, 2-bromo, 4-tertbuyl, 5-nitro phenol methanol solvate, (111.3 g, 0.59.9 mmol) was charged to a 1 L round bottom flask, followed by heptane (500 mL). The slurry is heated to 64° C. to obtain a clear solution. The solvent was distilled under reduced pressure (649 mbar) for 30 minutes and then stripped to dryness. This procedure was repeated three times until no MeOH was detected by 1H-NMR. The product was dried under high vacuum for 16 hours to give the product as a dark yellow semi solid. 1H-NMR (400 MHZ, DMSO-d6) δ 11.2 (bs, OH), 7.69 (s, 1H); 7.03 (s, 1H); 1.30 (s, 9H)
Reaction SMILES: Cl[C:2]1(Cl)[C:8](=[O:9])[CH:7]2[CH:3]1[CH2:4][CH2:5][CH:6]2[CH2:10][CH2:11][CH:12]([O:15][Si](C(C)(C)C)(C)C)[CH2:13][CH3:14].[C:24](O)(=O)C>[Zn]>[OH:15][CH:12]([CH2:13][CH3:14])[CH2:11][CH2:10][CH:6]1[CH2:5][CH2:4][CH:3]2[CH:7]1[CH2:24][C:8](=[O:9])[CH2:2]2
Reactant: CCC(CCC1CCC2C1C(=O)C2(Cl)Cl)O[Si](C)(C)C(C)(C)C
Reactant: CC(=O)O
Agent: [Zn]
Product: CCC(O)CCC1CCC2CC(=O)CC12

Procedure:
The procedure followed is the same as that described in Example 11 substituting the starting material prepared in Example 28, 6,6-dichloro-2-(3-[(1,1-dimethylethyl)dimethylsiloxy]pent-1-yl)bicyclo[3.2.0]heptan-7-one {7,7-dichloro-4-[3,[[(1,1-dimethylethyl)dimethylsilyl]oxy]pentyl]bicyclo[3.2.0]heptan-6-one} and isomers (2.4 g, 6.1 mmoles), glacial acetic acid (17 ml), and zinc powder (5 g). The crude product is chromatographed on silica gel and subsequently kugelrohred under vacuum leaving a clear, colorless oil (1.0 g, 4.8 mmoles).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:11](=[O:13])[CH:10]=[CH:9][C:8](=[O:14])[C:7]=2[N:6]=[CH:5][CH:4]=1.[F:15][C:16]([F:34])([F:33])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]=[CH:27][CH:28]=[N:29]N(C)C)=[O:18].C(OC(=O)C)(=O)C>CC#N.C1(C)C=CC=CC=1.[Pd]>[CH3:1][O:2][C:3]1[C:12]2[C:11](=[O:13])[C:10]3[C:26]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[NH:19][C:17](=[O:18])[C:16]([F:33])([F:15])[F:34])=[CH:27][CH:28]=[N:29][C:9]=3[C:8](=[O:14])[C:7]=2[N:6]=[CH:5][CH:4]=1
Reactant: CN(C)N=CC=Cc1ccccc1NC(=O)C(F)(F)F
Reactant: COc1ccnc2c1C(=O)C=CC2=O
Agent: [Pd]
Solvent: CC#N
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccnc2c1C(=O)c1c(-c3ccccc3NC(=O)C(F)(F)F)ccnc1C2=O
Yield: 8.8 %

Procedure:
3.5 g (16 mmol) of 4-methoxyquinoline-5,8-dione, 7 g (24 mmol) of 4-(2-trifluoroacetamidophenyl)-1-dimethylamino-1-aza-1,3-butadiene and 15 mL of acetic anhydride in 200 mL of CH3CN are refluxed for 18 hours. After evaporating off the solvent on a rotary evaporator and purifying by filtration through silica (99.5/0.5 CH2Cl2/MeOH), 3 g of adduct are obtained. This compound is dissolved in 150 mL of toluene, 6 g of Pd/C (10%) are added and the reaction medium is refluxed overnight. After filtering off and washing the residue with MeOH and then with CHCl3, the filtrate is concentrated on a rotary evaporator and then purified by flash chromatography on a column of silica (95/5 CH2Cl2/MeOH) to give 0.6 g of the compound in the form of a pale green powder.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].C(=O)([O-])[O-].[K+].[K+].[Cl:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>C(OCC)(=O)C.O>[Cl:16][CH2:17][CH2:18][C:19]([NH:4][C:3]1[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:2]=1[CH3:1])=[O:20]
Reactant: Cc1cccc(C)c1N
Reactant: O=C(Cl)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cccc(C)c1NC(=O)CCCl
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.8 %

Procedure:
A mixture of 2,6-dimethylaniline (60.5 g) and potassium carbonate (45 g) is dissolved in a 3:1 mixture of ethyl acetate and water (1,200 ml). To the ice-cooled mixture, 100 ml of an ethyl acetate solution of 3-chloropropionyl chloride (52.5 ml) is added dropwise under agitation. The reaction mixture is stirred for 3 hours at room temperature and the aqueous layer is subsequently separated. The organic layer is washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, and subsequently dried over Glauber's salt. Upon distilling off the solvent under vacuum, a colorless powder results. Recrystallization from ethanol provides a colorless needle in an amount of 96.5 g (yield: 90.8%). m.p. 131° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH3:31])=[N:8][N:9]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]3[C:19]([CH2:29][CH3:30])=[N:20][N:21]4[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[N:23][C:22]=34)=[CH:13][CH:12]=2)[CH:10]=1)=O)C.CC(C[AlH]CC(C)C)C.C1COCC1>ClCCl>[CH2:29]([C:19]1[C:18]([CH2:17][C:14]2[CH:15]=[CH:16][C:11]([N:9]3[CH:10]=[C:6]([CH2:4][OH:3])[C:7]([CH3:31])=[N:8]3)=[CH:12][CH:13]=2)=[C:22]2[N:23]=[C:24]([CH3:28])[CH:25]=[C:26]([CH3:27])[N:21]2[N:20]=1)[CH3:30]
Reactant: CCOC(=O)c1cn(-c2ccc(Cc3c(CC)nn4c(C)cc(C)nc34)cc2)nc1C
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCc1nn2c(C)cc(C)nc2c1Cc1ccc(-n2cc(CO)c(C)n2)cc1
Temperature: -70 °C
Reaction time: 2 h

Procedure:
1-[4-(2-Ethyl-5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-3-ylmethyl)-phenyl]-3-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (17) (618 mg, 1.53 mmol) was dissolved in 10 ml of dichloromethane and cooled at −70° C. A 1M solution of DIBAH in THF (3.1 ml, 3.1 mmol) was added and the reaction mixture was stirred for 2 h at −70° C. The mixture was quenched with water and diluted with dichloromethane. The mixture was filtrated and extracted with dichloromethane. Organic layer was washed with water and brine, dried over Na2 SO4 and concentrated to afford a yellow foam. The product was used in the next step without further purification.
Reaction SMILES: O[C@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O.[CH3:13][C:14]1[C:20]2[CH:21]=[CH:22][C:23]([O:25]C3OC(CO)C(O)C(O)C3O)=[CH:24][C:19]=2[O:18][C:16](=[O:17])[CH:15]=1>C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O.P([O-])([O-])([O-])=O>[CH3:13][C:14]1[C:20]2[CH:21]=[CH:22][C:23]([OH:25])=[CH:24][C:19]=2[O:18][C:16](=[O:17])[CH:15]=1
Reactant: Cc1cc(=O)oc2cc(OC3OC(CO)C(O)C(O)C3O)ccc12
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Agent: OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O
Product: Cc1cc(=O)oc2cc(O)ccc12
Reaction time: 0.33 h

Procedure:
α-Gal A was assayed using 4-methylumbelliferyl-α-D-galactopyranoside (4-MU-α-Gal) as previously described (Bishop, et al., 1980, In Enzyme Therapy in Genetic Diseases: 2. Desnick, R. J. (Ed.). Alan R. Liss, Inc. New York, p. 17). Briefly, a stock solution of 5 mM 4-MU was prepared in 0.1M citrate-phosphate buffer, pH 4.6 solubilized in an ultrasonic bath. The reaction mixtures containing 10-50 μl of enzyme preparation or cell extracts and 150 μl substrate, were incubated at 37° C. for 10-30 minutes. The reactions were terminated with the addition of 2.33 ml of 0.1M ethylenediamine. One unit of activity is that amount of enzyme which hydrolyzes 1 nmol of substrate/hour.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:13](=[O:16])[CH2:14][Cl:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)=O.C(N(CC)CC)C>C(OCC)(=O)C.C1(C)C=CC(S(N[C@H](C2C=CC=CC=2)[C@@H](C2C=CC=CC=2)N)(=O)=O)=CC=1.Cl[Rh+]C1(C)C(C)=C(C)C(C)=C1C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C@@H:13]([OH:16])[CH2:14][Cl:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)CCl)OCc1ccccc1
Agent: CC1=C(C)C(C)([Rh+]Cl)C(C)=C1C
Agent: Cc1ccc(S(=O)(=O)N[C@H](c2ccccc2)[C@H](N)c2ccccc2)cc1
Solvent: O=CO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(N[C@@H](Cc1ccccc1)[C@@H](O)CCl)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.9 %

Procedure:
(3S)-3-Benzyloxycarbonylamino-1-chloro-4-phenyl-2-butanone (331.8 mg, 1.0 mmol) and a formic acid/triethylamine azeotropic mixture (0.2 ml) were added to a solution of chloro(pentamethylcyclopentadienyl)rhodium (III) (1R,2R)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine (0.67 mg, 0.001 mmol, s/c=1000) in ethyl acetate (1.0 ml), followed by stirring at room temperature for 2 hours. After completion of the reaction, the reaction mixture was purified by silica gel column chromatography to give a desired compound, (2R, 3S)-3-benzyloxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane (320.1 mg; yield: 95.8%). HPLC analysis revealed that the production ratio of the desired (2R,3S)-form to the isomeric (2S,3S)-form, (2R,3S):(2S,3S), was 8.5:1. The results of elementary analysis were as follows.
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]1[C:9]([OH:10])=[C:8]([CH2:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)[C:7]([CH:21]([CH3:23])[CH3:22])=[N:6]1)#[N:2].Cl.N[C@H:26]([C:28]([NH2:30])=[O:29])[CH3:27].C([N:34](CC)C(C)C)(C)C.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[C:28]([CH2:26][CH2:27][NH:34][C:16](=[O:18])[C:15]1[CH:14]=[CH:13][C:12]([CH2:11][C:8]2[C:7]([CH:21]([CH3:23])[CH3:22])=[N:6][N:5]([CH2:4][CH2:3][C:1]#[N:2])[C:9]=2[OH:10])=[CH:20][CH:19]=1)(=[O:29])[NH2:30]
Reactant: CCN(C(C)C)C(C)C
Reactant: C[C@H](N)C(N)=O
Reactant: CC(C)c1nn(CCC#N)c(O)c1Cc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)c1nn(CCC#N)c(O)c1Cc1ccc(C(=O)NCCC(N)=O)cc1
Reaction time: 12 h

Procedure:
500 mg of compound 46 and 145 mg of □-alaninamide hydrochloride are introduced into 10 ml of dichloromethane, and 0.8 ml of N,N-diisopropylethylamine, 215 mg of 1-hydroxybenzotriazole and 306 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride are added. The solution is stirred for 12 h. The solution is concentrated and the crude product is purified by chromatography on silica gel (dichloromethane/methanol/glacial acetic acid 100:0:5→100:10:5). 440 mg of the desired compound 47 are obtained. C20H25N5O3 (383.5); MS (ESI+): 384.2 (M+H)+, tR=3.58 min (Gradient 3).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.Cl.Cl[CH2:11][C:12]([NH2:14])=[NH:13]>C1COCC1>[O:6]1[CH2:7][CH2:8][N:3]([CH2:11][CH:12]([NH2:14])[NH2:13])[CH2:4][CH2:5]1
Reactant: C1COCCN1
Reactant: N=C(N)CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NC(N)CN1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (2.4 g, 60 mmol, 60%) was added to the solution of morpholine (5.2 g, 60 mmol) in THF (40 mL, anhydrous) and stirred for 30 min at room temperature under nitrogen. Chloroacetamidine hydrochloride (2.58 g, 20 mmol) was added to this solution in one portion and stirred at 50° C. overnight. Solvent was removed under reduced pressure and the dark brown oily residue was directly used in the next step.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[CH:9]=[C:10]([S:15][C@@H:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][C@H:17]2[NH:25][C:26](OCC)=O)[CH:11]=[CH:12][C:13]=1[Cl:14]>C(OCC)C>[ClH:7].[Cl:7][C:8]1[CH:9]=[C:10]([S:15][C@@H:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][C@H:17]2[NH:25][CH3:26])[CH:11]=[CH:12][C:13]=1[Cl:14]
Reactant: CCOC(=O)N[C@@H]1Cc2ccccc2[C@H]1Sc1ccc(Cl)c(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CN[C@@H]1Cc2ccccc2[C@H]1Sc1ccc(Cl)c(Cl)c1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of LiAlH4 (0.34 g, 9.05 mmol) in dry diethyl ether under nitrogen was added a solution of (±) trans 1-(3,4-dichlorophenylthio)-2-ethoxycarbonylaminoindane (0.69 g, 1.81 mmol) in diethyl ether. After stirring at room temperature overnight, the reaction was worked up as described for Example 2, and then purified on a silica gel column using 1% ethanol in chloroform as eluant. The resulting oil (0.26 g) was extracted into n-pentane and treated with ethereal hydrogen chloride to give the title compound as a colourless solid, m.p. 143°-144° C. (from methanol/diethyl ether).
Reaction SMILES: [C-:1]#[N:2].[Na+].Br[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]#[N:13])[CH:7]=1.IC>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.ClCCl>[C:12]([C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[CH2:5][C:1]#[N:2])#[N:13]
Reactant: N#Cc1cccc(CBr)c1
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CI
Solvent: ClCCl
Solvent: O
Product: N#CCc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 102 %

Procedure:
To a solution of 9.8 g (200 mmole) of sodium cyanide and 1.61 g (5 mmole) of tetrabutylammonium bromide in 50 ml of water was added a solution of 19.61 g (100 mmole) of α-bromo-m-tolunitrile in 150 ml of dichloromethane. The mixture was stirred at room temperature for 24 hours. To this mixture was added 6.2 ml (100 mmole) of iodomethane. The mixture was stirred at room temperature for 3 hours. The layers were separated and the organic layer was dried over magnesium sulfate and was filtered. The filtrate was evaporated and the residue was triturated with petroleum ether and the insoluble material was collected to give 14.5 g of a white solid, mp-66-9° C.; 100% yield: 1H-NMR (300 MHz, CDCl3) δ (TMS) 3.80-3.90(s, 2H), 7.49-7.72(m, 4H).
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[C:3]([CH:11]=[O:12])[N:2]=1.[CH3:13][Mg]Br.C(OCC)C>O1CCCC1>[OH:12][CH:11]([C:3]1[N:2]=[CH:1][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=1)[CH3:13]
Reactant: O=Cc1cc2c(cn1)CCCC2
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)c1cc2c(cn1)CCCC2
Temperature: 25 °C
Yield: 99 %

Procedure:
5,6,7,8,-Tetrahydroisoquinoline-3-carbaldehyde (1.2 g, 7.44 mmole) is dissolved in 15 ml tetrahydrofuran at 0° C. in an oven dried 100 ml two neck round bottom flask under nitrogen. The solution is treated with methylmagnesium bromide in diethyl ether (3.7 ml, 11.2 mmole) followed by 10 ml diethyl ether. The reaction mixture is warmed to room temperature and then to reflux for 1 h. The mixture was cooled, is quenched with 20 ml 10% hydrochloric acid, and the pH is adjusted to 9 with 2N sodium hydroxide. The layers are separated, the aqueous layer is washed with 4×25 ml dichloromethane, and the combined organics are dried over potassium carbonate. The dried organics are concentrated in vacuo to give 1.30 g (99%) of the 3-(1-hydroxyethyl)-5,6,7,8-tetrahydroisoquinoline.
Reaction SMILES: [O:1]=[O+][O-].[C:4]([O:15][CH3:16])(=[O:14])[CH2:5][CH:6]([CH2:8][CH2:9][CH:10]=C(C)C)[CH3:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CO>[CH:10]([CH2:9][CH2:8][C@@H:6]([CH3:7])[CH2:5][C:4]([O:15][CH3:16])=[O:14])=[O:1]
Reactant: COC(=O)CC(C)CCC=C(C)C
Reactant: O=[O+][O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Product: COC(=O)C[C@H](C)CCC=O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Ozone generated by a Welsbach Ozonator was passed, at -78° C., into a solution of R(+) methyl citronellate (JACS 1968, 90, 3525; 3.0 g) in MeOH (30 mL) for 1.5 h. There was added more MeOH (60 mL) and triphenylphosphine (5.13 g, 1.2 eq.) and the mixture was stirred at room temperature for 45 min. The methanol was evaporated off, the residue was diluted with Et2O (100 mL) and the insoluble phosphine oxide filtered. The filtrate material was chromatographed on silica gel, eluting with a 1:3 mixture of ethyl acetate and hexane, to afford the compound as a colorless oil (1.25 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[N:13]=[CH:12][C:11]([S:14][C:15]3[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=3)=[CH:10][C:9]=2[O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[S:5][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1.CN(C=O)C>O>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[C:9]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:10][C:11]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:37][CH2:38][N:39]4[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]4)[CH:16]=3)=[CH:12][N:13]=2)[S:5][CH:6]=1
Reactant: Cc1csc(Nc2ncc(Sc3cccc(O)c3)cc2Oc2ccccc2)n1
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1csc(Nc2ncc(Sc3cccc(OCCN4CCCCC4)c3)cc2Oc2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.3 %

Procedure:
A mixture of 3-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)phenol (prepared according to Example 57; 70.0 mg, 0.172 mmol), potassium carbonate (71.2 mg, 0.515 mmol), 1-(2-chloroethyl)piperidine hydrochloride (31.6 mg, 0.172 mmol), and DMF (2 mL) was stirred at room temperature for 30 minutes and heated to 50° C. overnight. The reaction was cooled to room temperature and water (15 mL) was added and extracted with ether. A white precipitate formed in the ether layer and was filtered to afford N-(4-methylthiazol-2-yl)-3-phenoxy-5-(3-(2-(piperidin-1-yl)ethoxy)phenylthio)pyridin-2-amine (34.2 mg, 38.4% yield) as a white solid. 1H NMR (d6-DMSO) δ 9.56 (s, 1H), 8.29 (dd, 1H), 7.50 (dd, 1H), 7.28 (m, 2H), 7.11 (t, 1H), 7.00 (t, 1H), 6.82 (m, 2H), 6.65 (m, 1H), 6.58 (m, 1H), 6.54 (m, 1H), 6.35 (m, 1H), 3.79 (t, 2H), 2.23 (s, 3H), 2.17 (m, 4H), 2.12 (t, 2H), 1.38 (m, 4H), 1.31 (m, 2H); Mass spectrum (esi) m/z=519.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:16][C:17]1[C:23]([OH:24])=[CH:22][C:20]([NH2:21])=[C:19]([F:25])[CH:18]=1>CC(O)CCC>[ClH:1].[Cl:16][C:17]1[C:23]([OH:24])=[CH:22][C:20]([NH:21][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[C:19]([F:25])[CH:18]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Nc1cc(O)c(Cl)cc1F
Solvent: CCCC(C)O
Product: COc1cc2nccc(Nc3cc(O)c(Cl)cc3F)c2cc1OC
Product: Cl
Temperature: 120 °C
Yield: 67.4 %

Procedure:
A suspension of 4-chloro-6,7-dimethoxyquinoline (0.2 g, 0.89 mmol) and 4-chloro-2-fluoro-5-hydroxyaniline (173 mg, 1 mmol), (as described in EP 61741 A2), in 2-pentanol (2.5 ml) was heated at 120° C. for 6 hours. The resulting solid was collected by filtration, washed with isopropanol and then ether and dried under vacuum to give 4-(4-chloro-2-fluoro-5-hydroxyanilino)-6,7-dimethoxyquinoline hydrochloride (231 mg, 67%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][C@H:10]([C@@H:14]([OH:26])[C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)=[O:16])[C:9]2=[O:27])=[CH:4][CH:3]=1.[O-:28][C:29]#[N:30].[K+]>C(O)(C)=O.O.O>[C:29]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][C@H:10]([C@@H:14]([OH:26])[C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)=[O:16])[C:9]2=[O:27])=[CH:4][CH:3]=1)(=[O:28])[NH2:30]
Reactant: N#C[O-]
Reactant: N#Cc1ccc(NC(=O)[C@H](O)[C@H]2OCCN(c3ccc(N)cc3)C2=O)cc1
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1ccc(NC(=O)[C@H](O)[C@H]2OCCN(c3ccc(NC(N)=O)cc3)C2=O)cc1
Temperature: 45 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
To a solution of compound 26-5 (70 mg) in AcOH—H2O (6 mL-2 mL), was added a solution of potassium cyanate (KOCN; 31 mg) in water (2 mL). The reaction mixture was stirred at 40-50° C. for 3 hours and at room temperature overnight to precipitate. The resulting precipitate was collected by filtration, rinsed with waster and dried in vacuo to obtain compound 27-1 (70 mg) as a colorless amorphous solid.