Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([CH2:21][C:22]3[S:23][C:24]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)=[CH:25][CH:26]=3)[CH:15]=2)[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]1[OH:5].C([SiH](CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl>[OH2:2].[C@@H:3]1([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([CH2:21][C:22]3[S:23][C:24]([C:27]4[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=4)=[CH:25][CH:26]=3)[CH:15]=2)[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]1[OH:5].[C@@H:3]1([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([CH2:21][C:22]3[S:23][C:24]([C:27]4[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=4)=[CH:25][CH:26]=3)[CH:15]=2)[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]1[OH:5]
Reactant: COC1(c2ccc(C)c(Cc3ccc(-c4ccc(F)cc4)s3)c2)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc(-c2ccc(F)cc2)s1
Product: O
Temperature: 0 °C
Yield: 55.6 %

Procedure:
A solution of 3 (63.1 g) and triethylsilane (46.4 g) in dichloromethane (660 ml) was cooled by dry ice-acetone bath under argon atmosphere, and thereto was added dropwise boron trifluoride•ethyl ether complex (50.0 ml), and the mixture was stirred at the same temperature. The mixture was allowed to warm to 0° C. and stirred for 2 hours. At the same temperature, a saturated aqueous sodium hydrogen carbonate solution (800 ml) was added, and the mixture was stirred for 30 minutes. The organic solvent was evaporated under reduced pressure, and the residue was poured into water and extracted with ethyl acetate twice. The organic layer was washed with water twice, dried over magnesium sulfate and treated with activated carbon. The insoluble was filtered off and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (300 ml), and thereto were added diethyl ether (600 ml) and H2O (6 ml). The mixture was stirred at room temperature overnight, and the precipitate was collected, washed with ethyl acetate-diethyl ether (1:4) and dried under reduced pressure at room temperature to give 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene hemihydrate (33.5 g) as colorless crystals. mp 98-100° C. APCI-Mass m/Z 462 (M+NH4). 1H-NMR (DMSO-d6) δ 2.26 (3H, s), 3.13-3.28 (4H, m), 3.44 (1H, m), 3.69 (1H, m), 3.96 (1H, d, J=9.3 Hz), 4.10, 4.15 (each 1H, d, J=16.0 Hz), 4.43 (1H, t, J=5.8 Hz), 4.72 (1H, d, J=5.6 Hz), 4.92 (2H, d, J=4.8 Hz), 6.80 (1H, d, J=3.5 Hz), 7.11-7.15 (2H, m), 7.18-7.25 (3H, m), 7.28 (1H, d, J=3.5 Hz), 7.59 (2H, dd, J=8.8, 5.4 Hz). Anal. Calcd. for C24H25FO5S.0.5H2O: C, 63.56; H, 5.78; F, 4.19; S, 7.07. Found: C, 63.52; H, 5.72; F, 4.08; S, 7.00.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([N:8]([CH3:10])[CH3:9])[S:6][CH:7]=1.C1C[O:14]CC1.O>F[B-](F)(F)F.[Ag+]>[CH3:9][N:8]([C:5]1[S:6][CH:7]=[C:3]([CH2:2][OH:14])[N:4]=1)[CH3:10]
Reactant: C1CCOC1
Reactant: CN(C)c1nc(CCl)cs1
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: O
Product: CN(C)c1nc(CO)cs1
Reaction time: 1 h

Procedure:
A solution of 5.186 g (29 mmol) of 4-(chloromethyl)-2-(dimethylamino)thiazole in 100 ml of 1:1 THF/H2O was cooled to 0° C. and treated dropwise with a solution of 5.73 g (29 mmol) of silver tetrafluoroborate in 50 ml of 1:1 THF/H2O. After being stirred for 1 h, the mixture was filtered, the solid mass was washed with ethyl acetate, and the combined filtrates were concentrated in vacuo. The black residue was purified by silica gel chromatography to provide 0.80 g (17%) of the desired compound (Rf 0.24, 6% methanol in chloroform) as an oil. 1H NMR (CDCl3) δ 2.67 (br, 1 H), 3.09 (s, 6 H), 4.54 (s, 2 H), 6.35 (s, 1 H). Mass spectrum: (M+H)+ =159.
Reaction SMILES: Cl[C:2]1[N:3]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[C:4]2[C:9]([C:10]=1[C:11](Cl)=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.N1C=CC=CC=1.[NH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>C(Cl)(Cl)Cl.C(Cl)Cl>[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:11]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=3)[C:2]=2[N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[O:12])[CH2:25][CH2:24]1
Reactant: CN1CCNCC1
Reactant: C1CNCCN1
Reactant: COc1cccc(-n2c(Cl)c(C(=O)Cl)c3ccccc32)c1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COc1cccc(-n2c(N3CCNCC3)c(C(=O)N3CCN(C)CC3)c3ccccc32)c1
Reaction time: 1 h

Procedure:
To a solution of 3.2 g (10 mmols) of 2-chloro-1-(3-methoxyphenyl)-indole 3-carboxylic acid chloride in 20 ml of chloroform, a mixture pf 2.2 ml of N-methyl-piperazine, 2.4 ml of pyridine and 5 ml of chloroform was added while cooling. After standing for 1 hour at room temperature, the mixture was washed twice with water, and the solvent was evaporated in vacuo. The resinous residue, which was uniform according to thin-layer chromatography and consisted of 2-chloro-1-(3-methoxyphenyl)-indole 3-carboxylic acid (4-methyl)-piperazide, was dissolved in 40 ml of diglym, and after addition of 13 g (0.15 mol) of piperazine, the solution was heated to the boil. The cooled solution was diluted with methylene chloride, washed three times with water, and the solvent was eliminated in vacuo. The resinous residue was dissolved in chloroform, and an excess of ethanolic hydrochloric acid was added. The solvent was eliminated in vacuo, the crystallized residue was digested with acetone, suction-filtered and washed with acetone. The yield of faintly grey-colored dihydrochloride of the above compound amounted to 3.7 g (73% of the theoretical yield), m.p. 228°-230° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH2:5]Cl)=O.[CH2:7]([NH:11][C:12]([NH:14][C:15]([NH2:17])=[S:16])=[NH:13])[CH2:8][CH2:9][CH3:10]>CC(C)=O>[ClH:1].[CH2:7]([N:11]=[C:12]([NH2:13])[NH:14][C:15]1[S:16][CH:5]=[C:3]([CH2:2][Cl:1])[N:17]=1)[CH2:8][CH2:9][CH3:10]
Reactant: O=C(CCl)CCl
Reactant: CCCCNC(=N)NC(N)=S
Solvent: CC(C)=O
Product: CCCCN=C(N)Nc1nc(CCl)cs1
Product: Cl
Reaction time: 72 h

Procedure:
A solution of 1,3-dichloroacetone (3.02 g.) in acetone (10 ml.) was added to a stirred suspension of (N-n-butylamidino)thiourea (4.04 g.) in acetone (25 ml.) at room temperature. The resulting clear pale yellow solution was stirred for three days, then cooled in ice, and the precipitated solid filtered off and washed with acetone to give 2-(2-n-butylguanidino)-4-chloromethylthiazole hydrochloride
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:17])=[C:4]([C:8]([N:10]2[CH2:15][CH2:14][NH:13][C:12](=O)[CH2:11]2)=[O:9])[CH:5]=[CH:6][CH:7]=1.F[B-](F)(F)F.C[O+](C)C.[S:27]1[CH:31]=[CH:30][N:29]=[C:28]1[C:32]([NH:34][NH2:35])=O.C(O)CCC>ClCCl>[Cl:1][C:2]1[C:3]([CH3:17])=[C:4]([C:8]([N:10]2[CH2:15][CH2:14][N:13]3[C:32]([C:28]4[S:27][CH:31]=[CH:30][N:29]=4)=[N:34][N:35]=[C:12]3[CH2:11]2)=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cl)cccc1C(=O)N1CCNC(=O)C1
Reactant: NNC(=O)c1nccs1
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: CCCCO
Solvent: ClCCl
Product: Cc1c(Cl)cccc1C(=O)N1CCn2c(nnc2-c2nccs2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-[(3-Chloro-2-methylphenyl)carbonyl]-2-piperazinone (I134) (185 mg, 0.732 mmol) was suspended in dry Dichloromethane (DCM) (3 mL) before treating with trimethyloxonium tetrafluoroborate (137 mg, 0.879 mmol) and stirring for 16 hours at RT, under argon before adding 1,3-thiazole-2-carbohydrazide (I51) (157 mg, 1.098 mmol) and stirring for a further 4 hours. 1-Butanol (3.00 mL) was added then DCM was removed by evaporation and the residue was heated at 110° C. for 3 hours. The reaction was cooled to RT overnight and then worked up by diluting with DCM (50 ml), washing with saturated sodium bicarbonate solution (50 ml). The aqueous layer was extracted with DCM (2×30 ml), the combined extracts were washed with brine (30 ml), dried (MgSO4), filtered and evaporated to afford an orange gum, of crude material which was purified by MDAP. The desired fractions were isolated, combined and evaporated to afford a white solid, 125 mg. This was dried over the weekend at 40° C. and then dried overnight in a vacuum oven at 40° C. to afford the white solid of desired product in 115 mg.
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6]([OH:8])=[O:7].[Si:14]([O:21][C@H:22]1[CH2:31][C@H:30](O)[C@H:29]2[C:24]([CH:25]=[CH:26][C@H:27]([CH3:50])[C@@H:28]2[CH2:33][CH2:34][C@H:35]2[O:40][C:39](=[O:41])[CH2:38][C@H:37]([O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])[CH2:36]2)=[CH:23]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>>[Si:14]([O:21][C@H:22]1[CH2:31][C@H:30]([O:7][C:6](=[O:8])[CH:5]([O:4][C:3]2[CH:10]=[CH:11][CH:12]=[CH:13][C:2]=2[CH3:1])[CH3:9])[C@H:29]2[C:24]([CH:25]=[CH:26][C@H:27]([CH3:50])[C@@H:28]2[CH2:33][CH2:34][C@H:35]2[O:40][C:39](=[O:41])[CH2:38][C@H:37]([O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:44])[CH3:45])[CH2:36]2)=[CH:23]1)([C:17]([CH3:18])([CH3:19])[CH3:20])([CH3:16])[CH3:15]
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reactant: Cc1ccccc1OC(C)C(=O)O
Product: Cc1ccccc1OC(C)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 80.3 %

Procedure:
A procedure similar to that described in Example 1, above, was followed, but using 0.65 g of (2RS)-2-(2-methylphenoxy)propionic acid and 1.0 g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 1.04 g of the title compound as a colorless foam.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:24])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][C:15]([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:24])=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)Cc2ccc(Cl)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Cc1ccc(Cl)cc1)NC1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-[2-(4-chloro-phenyl)-acetylamino]-piperidine-1-carboxylic acid tert-butyl ester (0.55 g, 1.54 mmol) in dichloromethane (8.0 mL) cooled at 0° C. was treated with trifluoroacetic acid (20%) and warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and free based with 10% aqueous sodium bicarbonate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The crude product was purified on silica using gradient elution from ethyl acetate/methanol (2%) to ethyl acetate/methanol (20%). 1H-NMR (CDCL3) δ: 1.15-1.25 (2H, m), 1.80-1.90 (2H, m), 2.60-2.75 (2H, m), 2.90-3.10 (2H, m), 3.5 (2H, s), 3.85 (1H, m), 5.20 (1H, d), 7.15-7.35 (4H, m). ESI-MS m/z: 253 (M+1), UV retention time: 0.87 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)=[S:12]>C(N(CC)CC)C.C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[S:12])[CH:7]=1
Reactant: Cc1ccc(C(=S)CBr)cc1
Reactant: O=c1ncc(Cl)c[nH]1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=S)Cn2cc(Cl)cnc2=O)cc1
Temperature: 25 °C
Reaction time: 2.25 h
Yield: 63.3 %

Procedure:
A suspension of 5-chloropyrimidin-2-one (312 mg) and 2-bromo-4'-methylthioacetophenone (525 mg) in triethylamine (1 ml) and ethanol (20 ml) was stirred at ambient temperature for 2.25 hours. The resulting suspension was concentrated at reduced pressure then diluted with water (50 ml). The collected precipitate was crystallised from acetone to give the title pyrimidinone (404 mg,); m.p. 192°-197°, λmaxEtOH 229 nm (ε 14450), 312 nm (ε 21470), λinf 239.5 nm (ε 9930).
Reaction SMILES: C[O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][N:6]=[C:5]2[CH2:12][CH2:13][CH2:14][C:4]=12.Br>CC(O)=O>[N+:9]([C:8]1[C:3]([OH:2])=[C:4]2[CH2:14][CH2:13][CH2:12][C:5]2=[N:6][CH:7]=1)([O-:11])=[O:10]
Reactant: COc1c([N+](=O)[O-])cnc2c1CCC2
Agent: Br
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cnc2c(c1O)CCC2
Temperature: 130 °C

Procedure:
A mixture of 4-methoxy-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine (1.535 g, 7.905 mmol) in AcOH (2.6 mL) was treated with 48% aq. HBr (2.6 mL, 23 mmol). The flask was sealed and heated at 130° C. for 40 min. then allowed to cool. The mixture was then concentrated under reduced pressure and the residue was neutralized to pH=7-8 using 50% NaOH in a cold bath. The mixture was then concentrated under reduced pressure and the residue was diluted with MeOH and THF, dried, filtered and concentrated to give the sub-title compound as a light brown powder. LCMS calc. for C8H9N2O3(M+H)+: m/z=181.3. Found: 181.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@@H:9]([OH:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@@H:9]([O:12][S:21]([CH3:20])(=[O:23])=[O:22])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1CC[C@@H](O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CC[C@@H](OS(C)(=O)=O)CC1
Reaction time: 0.5 h

Procedure:
To a stirred, ice cold solution of 1.8 g of cis-4-hydroxy-cyclohexanecarboxylic acid ethyl ester, and 2.8 mL of triethylamine, in 25 mL of dichloromethane was added 0.85 mL of methane-sulfonyl chloride drop-wise over 10 min. The mixture was allowed to stir for 30 min, then concentrated under reduced pressure and diluted with 50 mL of ether and washed with 25 mL of 10% HCl, 25 mL of water, 25 mL of saturated sodium carbonate. The combined extracts were dried over magnesium sulfate and concentrated under reduced pressure. The crude mesylate, 2.5 g, was used without further purification: 1H NMR (400 MHz, CDCl3) 4.92 (m, 1H), 4.15 (q, 2H), 3.02 (s, 3H), 2.4 (m, 1H), 2.05 (m, 2H), 1.92 (m, 2H), 1.62-1.4 (complex m, 4H).
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([C:21]4([CH2:31][C:32]#[N:33])[CH2:24][C:23]([CH2:28][C:29]#[N:30])([CH2:25][C:26]#[N:27])[CH2:22]4)[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.FC(F)(F)C(O)=O.C(N)CN>CO>[N:12]1[C:11]2[NH:7][CH:8]=[CH:9][C:10]=2[C:15]([C:16]2[CH:17]=[N:18][N:19]([C:21]3([CH2:31][C:32]#[N:33])[CH2:22][C:23]([CH2:25][C:26]#[N:27])([CH2:28][C:29]#[N:30])[CH2:24]3)[CH:20]=2)=[N:14][CH:13]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CC(CC#N)(CC#N)C4)c3)ncnc21
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Solvent: CO
Product: N#CCC1(CC#N)CC(CC#N)(n2cc(-c3ncnc4[nH]ccc34)cn2)C1

Procedure:
2,2′,2″-1-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutane-1,3,3-triyltriacetonitrile (0.03 g, 0.00006 mol) was treated with trifluoroacetic acid (0.5 mL, 0.006 mol) at rt for 30 min and then evaporated to dryness. The residue was mixed with ethylenediamine (0.2 mL, 0.003 mol) in MeOH (1 mL) at rt for 1 h. The reaction was evaporated to dryness and the residue was purified with prep. LCMS (pH=10) to give the desired product. LCMS calculated for C19H17N8(M+H)+: m/z=357. 1; Found: 357.4. 1H NMR (400 MHz, DMSO-d6): δ 12.06 (1H, br s), 8.79 (1H, s), 8.63 (1H, s), 8.38 (1H, s), 7.55 (1H, d, J=3.6 Hz), 7.01 (1H, d, J=3.6 Hz), 3.46 (2H, s), 3.03 (2H, s), 2.97 2H, d, J=15.2 Hz), 2.76 (2H, s), 2.57 (2H, d, J=15.2 Hz) ppm.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]2[C:15]([CH3:16])=[CH:14][C:13]([N+:17]([O-:19])=[O:18])=[CH:12][C:9]=2[N+:10]=1[O-:11])=O)C.[NH3:20]>CO>[C:4]([C:6]1[S:7][C:8]2[C:15]([CH3:16])=[CH:14][C:13]([N+:17]([O-:19])=[O:18])=[CH:12][C:9]=2[N+:10]=1[O-:11])(=[O:3])[NH2:20]
Reactant: CCOC(=O)c1sc2c(C)cc([N+](=O)[O-])cc2[n+]1[O-]
Reactant: N
Solvent: CO
Product: Cc1cc([N+](=O)[O-])cc2c1sc(C(N)=O)[n+]2[O-]
Reaction time: 5 h
Yield: 97 %

Procedure:
160 g (0.57 mol) of 2-ethoxycarbonyl-5-nitro-7-methyl-benzothiazole-N-oxide are initially introduced in 1.0 1 of methanol, 42 g (0.62 mol of NH:) of an aqueous ammonia solution are added and the mixture is stirred at 20° C. to 25° C. for 5 hours. The crystalline product is isolated by filtering off with suction. 140 g (96 % of theory) of 2-carbamyl-5-nitro-7-methyl-benzothiazole-N-oxide of melting point >250° C. are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:47]=[CH:46][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([NH:31][CH2:32][CH2:33][CH2:34][N:35]([CH2:41][C:42]([O:44]C)=[O:43])[CH2:36][C:37]([O:39]C)=[O:38])=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].[OH-].[Na+].O.Cl>C1COCC1.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([NH:31][CH2:32][CH2:33][CH2:34][N:35]([CH2:36][C:37]([OH:39])=[O:38])[CH2:41][C:42]([OH:44])=[O:43])=[O:30])[CH:25]=3)[CH:19]=2)=[CH:46][CH:47]=1)=[O:11]
Reactant: COC(=O)CN(CCCNC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)ccn2)c1)CC(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCCN(CC(=O)O)CC(=O)O)c[nH]4)c3)cc2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of dimethyl 2,2′-[(3-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}propyl)imino]diacetate (100 mg, 0.15 mmol) in a mixture of THF/MeOH (5 ml/5 ml) was added 1M NaOH solution (1 ml, 1 mmol). The mixture was stirred at room temperature for 4 hours and poured into 50 ml of water. 1M HCl was added dropwise with vigorous stirring until pH=5. The precipitates were filtered, washed with water and dried in vacuo to give 2,2′-[(3-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}propyl)imino]diacetic acid as white solid. Yield: 82 mg, 78%.
Reaction SMILES: I[N:2]1[C:7]([OH:8])=[C:6]2[CH:9]=[C:10]([NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[N:11]=[C:5]2[N:4]=[CH:3]1.[C:19]([NH:25][C@H:26]([C:33]([O:35][CH3:36])=[O:34])[CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])(=[O:24])[CH2:20][CH2:21][C:22]#[CH:23].C(N(CC)CC)C.O>CN(C)C=O.[Cu]I>[OH:8][C:7]1[N:2]([C:23]#[C:22][CH2:21][CH2:20][C:19]([NH:25][C@H:26]([C:33]([O:35][CH3:36])=[O:34])[CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[O:24])[CH:3]=[N:4][C:5]2=[N:11][C:10]([NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:9][C:6]=12
Reactant: CC(C)(C)C(=O)Nc1cc2c(O)n(I)cnc-2n1
Reactant: C#CCCC(=O)N[C@@H](CCC(=O)OC)C(=O)OC
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CC[C@H](NC(=O)CCC#Cn1cnc2nc(NC(=O)C(C)(C)C)cc-2c1O)C(=O)OC
Reaction time: 2 h

Procedure:
To a mixture of 3.6 g (10 mmol) of well-dried 3-iodo-4-hydroxy-6-pivaloylaminopyrrolo[2,3-d]pyrimidine in 40 mL of dimethylformamide are added 4.0 g (13.19 mmol) of dimethyl N-(pent-4-ynoyl)-L-glutamate, 0.38 g of copper (I) iodide, 3 mL of triethylamine, and 1.0 g of tetrakis-(triphenylphosphine)palladium. This mixture is stirred at ambient temperatures for two hours and then poured into 500 mL of water. The solid is collected by filtration, air dried, and then refluxed in 200 mL of methanol. The mixture is cooled and the solid collected by filtration, dissolved in two liters of 10% methanol in methylene chloride, and chromatographed over silica. Initial black bands are rechromatographed and the combined colorless bands from the first and second runs are evaporated to give dimethyl N-[5-(4-hydroxy-6-pivaloylaminopyrrolo[2,3-d] pyrimidin-3-yl)pent-4-ynoyl]-L-glutamate which can be purified further by recrystallization from 50% methanol in methylene chloride.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:30])([CH3:29])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[C:10]([CH:23](O)[C:24]([CH3:27])([CH3:26])[CH3:25])[CH:9]=1)([CH3:4])[CH3:3].CCN(S(F)(F)[F:37])CC.O>C1(C)C=CC=CC=1>[CH3:3][C:2]([Si:5]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[C:10]([CH:23]([F:37])[C:24]([CH3:26])([CH3:25])[CH3:27])[CH:9]=1)([CH3:29])[CH3:30])([CH3:1])[CH3:4]
Reactant: CCN(CC)S(F)(F)F
Reactant: COc1ccc(F)c(-c2ccc(CO[Si](C)(C)C(C)(C)C)cc2C(O)C(C)(C)C)c1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(F)c(-c2ccc(CO[Si](C)(C)C(C)(C)C)cc2C(F)C(C)(C)C)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
To a solution of 66.30B (0.400 g, 0.925 mmol) in toluene (10 mL) at −78° C. was added DAST (0.209 g, 1.29 mmol) dropwise. The reaction was stirred at −78° C. for 30 minutes and then warmed to 23° C. and stirred for an additional 2 hours. Water was added to quench the reaction mixture. The reaction was then extracted three times with EtOAc. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure and the product was then purified on silica gel (0-10% EtOAc in hexanes) to yield 66.30C as a colorless oil (0.400 g, 99% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12])[CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][S:8]2)=[CH:6][CH:7]=1
Reactant: CC(C)=CCSc1cccc(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)CCSc2cc(Br)ccc21
Yield: 86.6 %

Procedure:
A solution of 1-bromo-3-(3-methyl-but-2-enylsulfanyl)-benzene (5.651 g, 22 mmole) in 100 mL of toluene was treated with 5.433 g of p-toluenesulfonic acid monohydrate and heated at reflux for 15 hours. The mixture was diluted with 100 mL of water, neutralized with solid sodium bicarbonate and extracted with two 100 mL portions of ethyl acetate. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil. The product was purified by short path distillation (T=190° C. at 1.08 Torr) to give 4.902 g of 7-bromo-4,4-dimethyl-thiochroman as a pale yellow oil, which contained approximately 20% 5-bromo-4,4-dimethyl-thiochroman.
Reaction SMILES: C(COC)OC.[BH4-].[Na+].[C:9]([CH:13]([O:15][C:16]([C:19]([C:22]([C:25]([C:28]([C:31](OC)=[O:32])([F:30])[F:29])([F:27])[F:26])([F:24])[F:23])([F:21])[F:20])([F:18])[F:17])[F:14])([F:12])([F:11])[F:10].S(=O)(=O)(O)O>O>[C:9]([CH:13]([O:15][C:16]([C:19]([C:22]([C:25]([C:28]([CH2:31][OH:32])([F:29])[F:30])([F:27])[F:26])([F:24])[F:23])([F:21])[F:20])([F:18])[F:17])[F:14])([F:12])([F:11])[F:10]
Reactant: COC(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)OC(F)C(F)(F)F
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)OC(F)C(F)(F)F
Temperature: 80 °C
Yield: 76.1 %

Procedure:
A 5-L round-bottom flask equipped with a mechanical stirrer and nitrogen bubbler was charged with 1 L of glyme, sodium borohydride (76 grams, 2.0 moles) and heated to 80° C. CF3CFH—O—(CF2)5COOCH3 (713 grams, 1.67 mole), prepared as described in Part A, was added to the stirred slurry over a period of one hour. A mixture of concentrated sulfuric acid (198 grams) and water (1.0 L) was added to the reaction mixture. The lower phase was separated, and the solvent was removed by distillation. Further distillation provided 506 grams of CF3CFH—O—(CF2)5CH2OH (boiling point 173° C.), the structure of which was confirmed by Fourier Transform Infrared Spectroscopy (FTIR) and 1H and 19F Nuclear Magnetic Resonance (NMR) Spectroscopy.