Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC[O:4][C:5]1[CH:6]=[C:7]([C:11]2[N:15]=[C:14]([C:16]3[S:20][C:19]([NH:21][C:22]4[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=4)=[N:18][C:17]=3[NH2:34])[O:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1.FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>O1CCOCC1>[NH2:34][C:17]1[N:18]=[C:19]([NH:21][C:22]2[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=2)[S:20][C:16]=1[C:14]1[O:13][N:12]=[C:11]([C:7]2[CH:6]=[C:5]([OH:4])[CH:10]=[CH:9][CH:8]=2)[N:15]=1
Reactant: COCOc1cccc(-c2noc(-c3sc(Nc4cc(OC)c(OC)c(OC)c4)nc3N)n2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: COc1cc(Nc2nc(N)c(-c3nc(-c4cccc(O)c4)no3)s2)cc(OC)c1OC
Temperature: 15 °C
Reaction time: 2 h
Yield: 33 %

Procedure:
To a solution of 200 mg (0.412 mmol) of 5-[3-(3-methoxymethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-N2-(3,4,5-trimethoxy-phenyl)-thiazole-2,4-diamine (prepared in Example B(4)) in 8 mL of 50% aqueous dioxane was added trifluoroacetic acid (8 mL) with water bath cooling at 15° C. After 2 hours at room temperature, toluene was added, and the solution was concentrated in vacuo with the water bath at 22° C. With five milliliters of solvent left, the solution was poured into cold aqueous sodium bicarbonate. This solution was extracted with two portions of dichloromethane, which was subsequently washed with brine and dried over sodium sulfate. Radial silica chromatography eluting with 5-10% methanol/dichloromethane gave 3-{5-[4-amino-2-(3,4,5-trimethoxy-phenylamino)-thiazol-5-yl]-[1,2,4]oxadiazol-3-yl}-phenol (60 mg) as a pale-yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](I)[S:9][CH:10]=1)=[O:5])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:31]([Si:33]([CH3:36])([CH3:35])[CH3:34])#[CH:32]>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:34][Si:33]([CH3:36])([CH3:35])[C:31]#[C:32][C:8]1[S:9][CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]=1
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)c1csc(I)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1csc(C#C[Si](C)(C)C)n1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
4-Ethoxycarbonyl-2-iodothiazole (6.39 g) was suspended in 60 ml of triethylamine, and 253 mg of palladium acetate and 592 mg of triphenylphosphine, and 6.37 ml of ethynyltrimethylsilane were added to the suspension under an argon atmosphere, followed by stirring at 80° C. for 2 hr. The reaction solution was concentrated under the reduced pressure, ethyl acetate and brine were added to the concentrate, and the mixture was adjusted to pH 3.0 by the addition of 1 N aqueous hydrochloric acid. The mixture was extracted twice with ethyl acetate and was washed with brine. The organic layer was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1) to give 3.97 g of 2-(2-trimethylsilylethynyl)-4-ethoxycarbonylthiazole. This compound was dissolved in 30 ml of methanol, and the solution was cooled in ice. Potassium carbonate (220 mg) was added to the cooled solution, and the mixture was stirred at room temperature for 30 min. Brine was added to the reaction solution, and the mixture was extracted twice with ethyl acetate and was washed with brine. The organic layer was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under the reduced pressure to give 2.50 g of 2-ethynyl-4-methoxycarbonylthiazole.
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([C:9]1[N:13]=[C:12]([NH:14]C=O)[S:11][N:10]=1)[C:6]([OH:8])=[O:7])[CH3:2].[OH-].[Na+].Cl>C(OCC)(=O)C>[CH2:1]([O:3][N:4]=[C:5]([C:9]1[N:13]=[C:12]([NH2:14])[S:11][N:10]=1)[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCON=C(C(=O)O)c1nsc(NC=O)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCON=C(C(=O)O)c1nsc(N)n1
Reaction time: 2 h
Yield: 75 %

Procedure:
A mixture of 2-ethoxyimino-2-(5-formamido-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer) (4.4 g) and 1 N aqueous solution of sodium hydroxide (54 ml) was stirred for 2 hours at 50° to 55° C. The mixture was cooled in an ice bath, acidified with hydrochloric acid (5.4 ml) and extracred with ethyl acetate. The extract was dried over magnesium sulfate and evaporated to dryness. The residue was triturated with diethyl ether to give 2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer) (2.92 g), mp. 168° to 170° C. (dec.).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([OH:22])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=1O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[CH3:20][O:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]2[C:14]=1[O:22][C@@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])[CH2:11][CH2:12]2
Reactant: COc1cccc(CC[C@H](O)CO[Si](C)(C)C(C)(C)C)c1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1cccc2c1O[C@@H](CO[Si](C)(C)C(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.9 %

Procedure:
To a solution of 2-((3S)-4-{[tert-butyl(dimethyl)silyl]oxy}-3-hydroxybutyl)-6-methoxyphenol (6.90 g, 21.1 mmol) in toluene (250 mL) cooled to 0° C. was added triphenylphoshine (6.10 g, 23.2 mmol) followed by dropwise addition of diethyl azodicarboxylate (4.05 g, 23.2 mmol). The reaction mixture was allowed to stir at room temperature for 15 min. The reaction mixture was quenched by the addition of water (300 mL). The aqueous layer was separated and extracted with diethyl ether (2×150 mL). The combined organic extracts were washed with water (200 mL), aqueous sodium chloride (300 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:4) provided 4.94 g (76%, 40% ee) of tert-butyl(dimethyl)silyl [(2R)-8-methoxy-3,4-dihydro-2H-chromen-2-yl]methyl ether as a colorless oil. [α]D25=−25.84 (c 10.82 in chloroform, 40% ee); Rf=0.68 (silica, ethyl acetate:hexanes 1:4); Anal. Calcd. for C17H28O3Si.0.1 H2O: C, 65.8; H, 9.16. Found: C, 65.75; H, 8.88.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([O:10][C:11]3[N:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13]([OH:15])=O)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([OH:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=1>>[O:1]1[C:5]2[CH:6]=[C:7]([O:10][C:11]3[N:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([OH:31])([CH3:29])[CH3:30])=[CH:24][CH:23]=3)=[O:15])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC(C)(O)c1ccc(CN)cc1
Reactant: O=C(O)c1cccnc1Oc1ccc2ncoc2c1
Product: CC(C)(O)c1ccc(CNC(=O)c2cccnc2Oc2ccc3ncoc3c2)cc1

Procedure:
Prepared from 2-(Benzooxazol-6-yloxy)-nicotinic acid and 2-(4-aminomethyl-phenyl)-propan-2-ol. mp 92-4° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH3:25])[CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: Cc1ccc2c(c1)C(C)NCC2
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: Cc1ccc2c(c1)C(C)N(C(=O)c1cc3ncc(Br)cn3n1)CC2
Yield: 55 %

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1,7-Dimethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound.
Reaction SMILES: C[O:2][C:3](=[O:44])[CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH:17]([F:19])[F:18])=[CH:13][CH:14]=2)[C:9]([C:20]2[N:21]=[C:22]3[C:28]([C:29](=[O:35])[NH:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:27][N:26]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:23]3=[N:24][CH:25]=2)=[N:8]1.CO.[OH-].[Li+].Cl>C1COCC1.O>[C:31]([NH:30][C:29]([C:28]1[C:22]2[C:23](=[N:24][CH:25]=[C:20]([C:9]3[C:10]4[C:15](=[CH:14][CH:13]=[C:12]([O:16][CH:17]([F:18])[F:19])[CH:11]=4)[N:7]([CH2:6][CH2:5][CH2:4][C:3]([OH:44])=[O:2])[N:8]=3)[N:21]=2)[N:26]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[CH:27]=1)=[O:35])([CH3:32])([CH3:33])[CH3:34]
Reactant: COC(=O)CCCn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c2cc(OC(F)F)ccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCCC(=O)O)c4ccc(OC(F)F)cc34)nc12
Temperature: 75 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
In a round-bottomed flask, 4-{3-[7-tert-butylcarbamoyl-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-5-difluoromethoxy-indazol-1-yl}-butyric acid methyl ester (98 mg, 0.155 mmol) was suspended in THF (1.1 ml), methanol (1.1 ml) and water (1.1 ml). Then, aqueous 1.0 M lithium hydroxide (0.80 ml, 0.80 mmol) was added. The light yellow suspension was stirred at 75° C. for 8 h then cooled to room temperature and stirred overnight. The reaction was diluted with water and acidified with 1 M HCl until pH=˜2 then extracted with dichloromethane (3×). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was triturated with diethyl ether to afford 81 mg (85%) of 4-{3-[7-tert-butylcarbamoyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-5-difluoromethoxy-indazol-1-yl}-butyric acid as a brown powder.
Reaction SMILES: [CH3:1][Si:2]([CH3:14])([CH3:13])[CH2:3][CH:4]([C:11]#[N:12])[CH2:5][C:6]([O:8]CC)=[O:7].O.[OH-].[Li+].Cl>CO.COCCOC.O>[CH3:14][Si:2]([CH3:1])([CH3:13])[CH2:3][CH:4]([C:11]#[N:12])[CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)CC(C#N)C[Si](C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: COCCOC
Solvent: CO
Solvent: O
Product: C[Si](C)(C)CC(C#N)CC(=O)O
Yield: 99.5 %

Procedure:
A solution of ethyl 4-(trimethylsilyl)-3-cyanobutanoate (341 mg, 1.60 mmol) in methanol/1,2-dimethoxyethane/water (3:2:1, 4.2 ml) was added with lithium hydroxide monohydrate (135 mg, 3.21 mmol), and the mixture was refluxed by heating for 1 hour with stirring. The reaction mixture was cooled on ice, and added with aqueous hydrochloric acid (1 N), and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained crystals were purified by recrystallization, and the mother solution was subjected to purification by silica gel chromatography (2% methanol/chloroform) to obtain 4-trimethylsilyl-3-cyanobutanoic acid (295 mg, quant.) mentioned in the title as colorless scaly crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][NH:11][CH:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:31])[C:22]1[C:23](=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:24](N)=[O:25]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH2:16][CH2:17][CH2:18][CH2:19][N:20]3[C:24](=[O:25])[C:23]4[C:22](=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:21]3=[O:31])[CH:12]=2)=[CH:6][CH:7]=1
Reactant: NC(=O)c1ccccc1C(=O)NCCCCBr
Reactant: Clc1ccc(-c2c[nH]cn2)cc1
Agent: [H-]
Agent: [Na+]
Product: O=C1c2ccccc2C(=O)N1CCCCn1cnc(-c2ccc(Cl)cc2)c1
Yield: 37.4 %

Procedure:
Using the procedure of Stage A of Example 1, 12.2 g of the product of Stage A, 4.96 g of sodium hydride and 23.83 g of N-4-bromobutyl-phthalamide were reacted to obtain 9.7 g of the expected product.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[O:21][CH3:22])[N:4]([C@@H:23]2[CH2:31][CH2:30][CH2:29][C:28]3[N:27](S(C4C=CC(C)=CC=4)(=O)=O)[N:26]=[CH:25][C:24]2=3)[N:3]=1.O[Li].O>C1COCC1>[Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[O:21][CH3:22])[N:4]([C@@H:23]2[CH2:31][CH2:30][CH2:29][C:28]3[NH:27][N:26]=[CH:25][C:24]2=3)[N:3]=1
Reactant: COc1ccc(CNc2ncnc3c2c(Br)nn3[C@@H]2CCCc3c2cnn3S(=O)(=O)c2ccc(C)cc2)c(OC)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CNc2ncnc3c2c(Br)nn3[C@@H]2CCCc3[nH]ncc32)c(OC)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
To a solution of (R)-3-bromo-N-(2,4-dimethoxybenzyl)-1-(1-tosyl-4,5,6,7-tetrahydro-1H-indazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (400 mg, 0.626 mmol) in THF (6.3 mL) was added 1N LiOH.H2O (105 mg, 2.504 mmol), then the mixture was stirred for 8 h at 60° C. Removed the solvent under reduced pressure and extracted with DCM and the combined organic layer was washed with water, brine and dried over anhydrous Na2SO4. The organic layer was concentrated in vacuo and the residue (R)-3-bromo-N-(2,4-dimethoxybenzyl)-1-(4,5,6,7-tetrahydro-1H-indazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (280 mg, yield 92.3%) was used directly to next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH3:10].[Mg].[B:13](OC)([O:16]C)[O:14]C.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([B:13]([OH:16])[OH:14])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH3:10]
Reactant: CCOc1ccc(Br)cc1F
Reactant: COB(OC)OC
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCOc1ccc(B(O)O)cc1F
Temperature: -70 °C
Reaction time: 1 h
Yield: 116.6 %

Procedure:
100 ml of a THF solution of 22.8 g (104 mmol) of 3-fluoro-4-ethoxybromobenzene was dropped, while stirring, at 40 to 60° C. to 3.03 g (124.8 mmol) of dried turnings magnesium, and refluxed under heating after dropping for one hour. The solution was cooled by a coolant to −70° C. and, a THF solution of 16 ml (132.5 mmol) of trimethyl borate (THF: 70 ml) was dropped under stirring. After stirring at −70° C. for 3 hours, and further stirring at a room temperature for 20 hours, the reaction solution was cooled to 5° C., and 50 ml of 6M hydrochloric acid was added. After separating the organic layer, the aqueous layer was extracted with 100 ml of ethyl acetate. After mixing the organic layer, it was washed with water and then with an aqueous saturated sodium chloride solution successively and, after drying over anhydrous magnesium sulfate, concentrated under a reduced pressure, to obtain 22.3 g of crude 3-fluoro-4-ethoxyphenyl boronic acid. The obtained crude boronic acid derivative was used without purification for a second step.
Reaction SMILES: C[O-].[CH2:3]([C:5]1([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:14]2[C:13]3[NH:15][C:16]4[C:21]([C:12]=3[CH2:11][CH2:10][N+:9]=2[CH2:8][CH2:7][CH2:6]1)=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=4)[CH3:4].[Cl:29]([OH:33])(=[O:32])(=[O:31])=[O:30]>CO>[Cl:29]([O-:33])(=[O:32])(=[O:31])=[O:30].[CH2:3]([C:5]1([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:14]2[C:13]3[NH:15][C:16]4[C:21]([C:12]=3[CH2:11][CH2:10][N+:9]=2[CH2:8][CH2:7][CH2:6]1)=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=4)[CH3:4]
Reactant: [O-][Cl+3]([O-])([O-])O
Agent: CCC1(CCC(=O)OC)CCC[N+]2=C1c1[nH]c3ccc(Br)cc3c1CC2
Agent: C[O-]
Solvent: CO
Product: [O-][Cl+3]([O-])([O-])[O-]

Procedure:
0.1 g. of 1-ethyl-1-(2'-methoxycarbonylethyl)-9-bromo-1,2,3,4,6,7-hexahydro-12H-indolo[2,3-a]quinolizin-5-ium methoxide (prepared as described in Example 7) are suspended in 1 ml. of methanol, and the pH of the suspension is adjusted to 6 by introducing a 70% aqueous perchloric acid solution. The separated crystalline product is filtered off, washed with a small amount of methanol and dried. In this way 0.095 g. of 1-ethyl-1-(2'-methoxycarbonylethyl)-9-bromo-1,2,3,4,6,7-hexahydro-12H-indolo[2,3-a]quinolizin-5-ium perchlorate are obtained; m.p.: 221°-222° C. (after recrystallization from methanol).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[O:11][S:12]([CH3:15])(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([O:29][CH2:30][CH3:31])(=[O:28])CS.[O-]CC.[Na+]>CN(C)C=O>[CH2:1]([O:8][CH2:9][CH:10]([CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[O:11][S:12][CH2:15][C:25]([O:29][CH2:30][CH3:31])=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CS
Reactant: CC(C)(C)[Si](C)(C)OCC(COCc1ccccc1)OS(C)(=O)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CSOC(COCc1ccccc1)CO[Si](C)(C)C(C)(C)C
Temperature: 80 °C
Reaction time: 6 h

Procedure:
1-O-benzyl-3-O-t-butyldimethylsilyl-2-O-mesylglycerol (0.83 g) was dissolved in N,N-dimethylformamide (5 ml), and ethyl thioglycolate (0.34 ml) and sodium ethoxide (sodium 0.07 g/ethanol 5 ml) were added thereto, and the mixture stirred at 80° C. for 6 hours. After removing the solvent by evaporation under reduced pressure, water was added to the residue and the solution was extracted with ethyl ether (20 ml×3).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](F)([F:12])[C:7](F)([F:14])[CH:6]=[CH:5]2.[NH4+].[Cl-].[NH4+].[OH-]>[Zn].C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([F:12])=[C:7]([F:14])[CH:6]=[CH:5]2
Reactant: FC1(F)C=Cc2cc(Br)ccc2C1(F)F
Agent: [Cl-]
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Fc1ccc2cc(Br)ccc2c1F
Temperature: 25 °C
Yield: 83.3 %

Procedure:
Zinc (7.18 g, 110 mmol) was added in two portions (4.74 g and 2.44 g) to a stirred mixture of 20.1 g (71.4 mmol) of 6-bromo-1,1,2,2-tetrafluoro-1,2-dihydronaphthalene, 45 ml of THF, 20.1 g of NH4Cl, and 90 ml of NH4OH that was cooled in an ice bath. The mixture was allowed to warm slowly to room temperature. After 5 hours reaction time, the zinc was removed by filtration. The phases were separated, and the aqueous layer was extracted three times with hexanes. The combined organic phase was washed twice with brine and dried over MgSO4. The MgSO4 was filtered off, and the solvent was removed under vacuum. Crude 6-bromo-1,2-difluoronaphthalene (16.7 g) containing 15% impurities (estimated) remained. The estimated yield of the crude 6-bromo-1,2-difluoronaphthalene was 86%. The crude yellow solid was sublimed at 70-80° C. Off-white needles (14.5 g, 59.5 mmol, 83% yield) were collected.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:12][C:11](C(O)=O)([C:13]([OH:15])=[O:14])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>N1C=CC=CC=1>[CH2:1]([O:8][CH:9]1[CH2:10][CH:11]([C:13]([OH:15])=[O:14])[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C1(C(=O)O)CC(OCc2ccccc2)C1
Solvent: c1ccncc1
Product: O=C(O)C1CC(OCc2ccccc2)C1
Temperature: 25 °C
Yield: 94.7 %

Procedure:
A solution of 3-(benzyloxy)cyclobutane-1,1-dicarboxylic acid (1.5 g, 5.99 mmol) in pyridine (3 mL) was heated in a 120° C. oil bath for 12 h. The mixture was cooled to RT and the pyridine was removed under vacuum. Toluene (10 mL) was added and the solution was washed with 1N HCl (3×), dried (MgSO4), filtered, and concentrated in vacuo to give product as a brown oil (1.17 g, 95%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][S:10][C:11]#[N:12])=[CH:4][CH:3]=1.[OH-].[Na+].[BrH:16]>C(O)(=O)C>[Br:16][C:11]1[S:10][CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[N:12]=1
Reactant: N#CSCC(=O)c1ccc(Br)cc1
Reactant: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Brc1ccc(-c2csc(Br)n2)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 84 %

Procedure:
A suspension of 2-(4-bromophenyl)-2-oxoethyl thiocyanate (5.12 g, 20.0 mmol), prepared in the previous step, in 30 mL of 30% hydrogen bromide in acetic acid was stirred under nitrogen at room temperature for 7 h. The yellow suspension was poured into 200 mL of 1 N NaOH (exotherm) and the mixture stirred at room temperature for 17 h. The solid present was collected by filtration, rinsed with water, ice-cold ethanol, hexane and then dried under high vacuum to give 2-bromo-4-(4-bromophenyl)-1,3-thiazole (5.36 g, 84%) as a light yellow solid, mp 117-119° C.; MS (ES) m/z 318/320/322 [M+H]+.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Br:12])=[CH:4][CH:3]=1.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1B(O)O.C([O-])([O-])=O.[Na+].[Na+].CCO>C1(C)C=CC=CC=1>[Br:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([C:14]2[S:13][CH:17]=[CH:16][CH:15]=2)=[CH:3][CH:4]=1
Reactant: OB(O)c1cccs1
Reactant: Brc1ccc(Br)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2cccs2)c2ccccc12
Temperature: 100 °C
Yield: 73 %

Procedure:
A mixture of 28.6 g (100 mmol) of 1,4-dibromonaphthalene, 15.35 g (120 mmol) of thiophen-2-ylboronic acid, 2.31 g (2 mmol) of tetrakis(triphenyl phosphine)palladium, 75 ml of 2M Na2CO3, 150 ml of EtOH and 300 ml toluene was degassed and placed under nitrogen, and then heated at 100° C. for 4 h. After finishing the reaction, the mixture was allowed to cool to room temperature. The organic layer was extracted with ethyl acetate and water, dried with anhydrous magnesium sulfate, the solvent was removed and the residue was purified by column chromatography on silica(hexane-dichloromethane) to give product (21.1 g, 73 mmol, 73%) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:14]([CH3:15])[CH:13]=[N:12][CH:11]=2)=[O:9])=[CH:4][N:3]=1.[CH3:16][OH:17]>>[CH3:16][O:17][C:2]1[N:3]=[CH:4][C:5]([C:8]([C:10]2[N:14]([CH3:15])[CH:13]=[N:12][CH:11]=2)=[O:9])=[CH:6][CH:7]=1
Reactant: CO
Reactant: Cn1cncc1C(=O)c1ccc(Cl)nc1
Product: COc1ccc(C(=O)c2cncn2C)cn1
Temperature: 75 °C
Reaction time: 4 h

Procedure:
In a 50-mL round-bottom flask was placed a solution of Na (260 mg, 11.3 mmol) in methanol (15 mL) and the solution was stirred for 30 minutes at room temperature. Then 2-chloro-5-[(1-methyl-1H-imidazol-5-yl)carbonyl]pyridine (250 mg, 1.13 mmol, Intermediate 4, step c) was added. The resulting mixture was stirred for 4 hours at 75° C. and concentrated under vacuum. The residue was purified by flash column chromatography (silica gel, 100:0-20:1 CH2Cl2:MeOH) to give the title compound as a light yellow solid.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][CH:9]([O:12][CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][CH2:7]1)=O)C.[OH-].[K+].[ClH:28]>C(O)(C)C>[ClH:28].[C:20]1([CH:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:12][CH:9]2[CH2:10][CH2:11][NH:6][CH2:7][CH2:8]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)N1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Yield: 71 %

Procedure:
A solution of 1-ethoxycarbonyl-4-diphenylmethoxypiperidine (60 g; 0.176 moles) and 85% potassium hydroxide (116 g; 1.76 moles) in isopropanol (600 ml) was boiled under reflux for 6 hours. After cooling, concentrated hydrochloric acid was added until pH=2 and the solvent removed in vacuo. The resulting residue was dissolved in a small quantity of water, washed with diethyl ether and the aqueous solution was made alkaline with aqueous sodium hydroxide solution and extracted with methylene chloride. The organic solution was dried (Na2SO4), the solvent removed in vacuo and the residual oil treated with ethanolic hydrogen chloride solution. 4-Diphenylmethoxy-piperidine hydrochloride (38 g; yield 71%) was obtained.