Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])(=[O:16])=[O:15])=[CH:10][CH:9]=1.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][NH2:40])[CH:34]=1>>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([S:14]([CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:32]=[CH:31][C:27]([C:28]([NH:40][CH2:39][C:35]4[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=4)=[O:29])=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])(=[O:16])=[O:15])=[CH:12][CH:13]=1
Reactant: NCc1cccnc1
Reactant: Cc1oc(-c2ccc(C(=O)O)cc2)nc1CS(=O)(=O)c1ccc(Cl)cc1
Agent: O=C(Cl)C(=O)Cl
Product: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)c1ccc(Cl)cc1
Yield: 82.5 %

Procedure:
Reaction of oxalyl chloride (60 λL, 0.69 mmol) and benzoic acid 20 (179 mg, 0.46 mmol) with subsequent coupling to 3-pyridinylmethylamine (51 λL, 0.50 mmol) gave benzamide 21 (183 mg, 85%) as a white powder: mp (EtOAc) 220-222° C.; 1H NMR δ 9.20 (t, J=5.8 Hz, 1H, CONH), 8.56 (d, J=1.6 Hz, 1H, H-2′), 8.51 (dd, J=4.7, 1.6 Hz, 1H, H-6′), 8.00 (d, J=8.6 Hz, 2H, H-2, H-6), 7.88 (d, J=8.6 Hz, 2H, H-3, H-5), 7.81 (ddd, J=8.7, 2.4, 1.9 Hz, 2H, H-2″, H-6″), 7.74 (br dt, J=7.9, 1.8 Hz, 1H, H-4′), 7.70 (ddd, J=8.7, 2.4, 1.9 Hz, 2H, H-3″, H-5″), 7.36 (dd, J=7.9, 4.7 Hz, 1H, H-5′), 4.73 (s, 2H, CH2SO2), 4.51 (d, J=5.8 Hz, 2H, CH2N), 2.21 (s, 3H, CH3); 13C NMR δ 165.4, 158.0, 150.0, 148.8, 148.0, 139.0, 137.3, 135.4, 135.1, 134.8, 130.2 (2), 129.2 (2), 128.7, 128.0 (2), 125.6, 125.3 (2), 123.4, 52.7, 40.4, 9.7; MS m/z 483.3 (MH+, 100%). Anal. calcd for C24H20ClN3O4S: C, 59.81; H, 4.18; N, 8.72. Found: C, 60.12; H, 4.09; N, 8.82%.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[C:7]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:8]=1)=[O:2].P([O-])(O)(O)=[O:20].[Na+].OO.Cl([O-])=O.[Na+].Cl>C(#N)C.O.C(Cl)(Cl)Cl>[CH3:13][O:12][C:10]([CH2:9][C:7]1[CH:8]=[C:3]([CH:4]=[CH:5][C:6]=1[O:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:1]([OH:20])=[O:2])=[O:11]
Reactant: O=P([O-])(O)O
Reactant: COC(=O)Cc1cc(C=O)ccc1OCC(C)C
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: COC(=O)Cc1cc(C(=O)O)ccc1OCC(C)C
Temperature: 7.5 °C
Reaction time: 3.5 h
Yield: 72.8 %

Procedure:
In 8 ml of acetonitrile is dissolved 0.80 g of methyl 2-(5-formyl-2-isobutoxyphenyl)acetate. After successively adding 2.03 g of sodium dihydrogen-phosphate dissolved in 25 ml of water, 0.69 ml of 30% aqueous hydrogen peroxide and 0.73 g of sodium chlorite dissolved in 15 ml of water at a temperature of 5-10° C., the mixture thus obtained is stirred at 5-10° C. for 3.5 hours. Chloroform and water are added to the reaction mixture, pH is adjusted to 2.0 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. Thus, 0.62 g of 3-(methoxycarbonylmethyl)-4-isobutoxybenzoic acid is obtained as a colorless crystalline product.
Reaction SMILES: C([O:8][C:9]1[CH:27]=[CH:26][C:12]([CH2:13][C:14]2[CH:18]=[C:17]([C:19]3[C:20]([NH2:25])=[N:21][CH:22]=[CH:23][CH:24]=3)[O:16][N:15]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.FC(F)(F)C(O)=O.C1(SC)C=CC=CC=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[NH2:25][C:20]1[C:19]([C:17]2[O:16][N:15]=[C:14]([CH2:13][C:12]3[CH:26]=[CH:27][C:9]([OH:8])=[CH:10][CH:11]=3)[CH:18]=2)=[CH:24][CH:23]=[CH:22][N:21]=1
Reactant: Nc1ncccc1-c1cc(Cc2ccc(OCc3ccccc3)cc2)no1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Nc1ncccc1-c1cc(Cc2ccc(O)cc2)no1
Reaction time: 2 h
Yield: 99.8 %

Procedure:
To a mixture of 3-(3-(4-benzyloxy-benzyl)-isoxazol-5-yl)-pyridin-2-ylamine (32 mg, 0.090 mmol) described in Example 1 and trifluoroacetic acid (1 mL) was added thioanisole (45 mg, 0.36 mmol) at room temperature, which was stirred for 2 hours at the same temperature. To a mixture of saturated aqueous sodium hydrogencarbonate solution and ethyl acetate was added the reaction mixture. The organic layer was separated and washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=4:1) to obtain the title compound (24 mg, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:25])=[C:6]([C@:8]23[O:16][CH2:15][CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:17]C(=O)OC(C)(C)C)=[N:9]3)[CH:7]=1.[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([C:33](O)=[O:34])=[N:31][CH:32]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:17][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:14][CH2:15][O:16][C@:8]2([C:6]2[CH:7]=[C:2]([NH:1][C:33](=[O:34])[C:30]3[CH:29]=[CH:28][C:27]([Cl:26])=[CH:32][N:31]=3)[CH:3]=[CH:4][C:5]=2[F:25])[N:9]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(N)ccc3F)OCC[C@H]2CS1
Reactant: O=C(O)c1ccc(Cl)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC1=N[C@@]2(c3cc(NC(=O)c4ccc(Cl)cn4)ccc3F)OCC[C@H]2CS1
Yield: 48 %

Procedure:
A solution of (±)-tert-butyl (4aR,7aR)-7a-(5-amino-2-fluorophenyl)-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-2-ylcarbamate from step G of Preparation 1 (9 mg), 5-chloropicolinic acid (7 mg), HATU (14 mg), and DIEA (11 μL), in DMF (0.12 mL) was stirred at rt for 2 h, and the crude reaction mixture was subjected to preparative HPLC eluting with 0-100% B (A: 95% H2O/5% MeCN, 10 mM NH4OAc; B: 5% H2O/95% MeCN, 10 mM NH4OAC over 12 min period to give the title compound as a white foam (6 mg, 48%). 1H NMR (500 MHz, CDCl3) δ 9.87 (1H, s), 8.60 (1H, s), 8.26 (1H, d, J=8.5 Hz), 8.02 (1H, br d), 7.92 (1H, dd, J=2.0, 8.0 Hz), 7.72 (1H, m), 7.14 (1H, t, J=10.5 Hz), 4.20 (2H, m), 3.32 (1H, m), 3.02 (1H, m), 2.90 (1H, m), 2.40 (1H, m), 2.24 (1H, m), and 1.51 (9H, s). MS (M+H)+:505.3.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:13][C:12]([C:14]2[N:15]=[CH:16][N:17]([C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]4[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=4)[N:20]=3)[CH:18]=2)=[N:11][C:10]=1[CH3:39])(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:39][C:10]1[N:11]=[C:12]([C:14]2[N:15]=[CH:16][N:17]([C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]4[CH:30]=[CH:31][C:32]([C:35]([F:37])([F:36])[F:38])=[CH:33][CH:34]=4)[N:20]=3)[CH:18]=2)[S:13][C:9]=1[S:6]([NH2:5])(=[O:8])=[O:7]
Reactant: Cc1nc(-c2cn(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)cn2)sc1S(=O)(=O)NC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(-c2cn(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)cn2)sc1S(N)(=O)=O
Yield: 99 %

Procedure:
To a stirred and cooled suspension of 4-methyl-2-{1-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-1H-imidazol-4-yl}-thiazole-5-sulfonic acid tert-butylamide (example 292) (0.295 g, 0.50 mmol) in dichloromethane (3 mL) was added TFA (3 mL) and the reaction mixture was allowed to stir at room temperature for 16 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane/diethyl ether and dried to yield the title compound as a white solid (0.264 g, 99%). MS (ISP) 534.2 [(M+H)+]; mp 187° C. (dec.).
Reaction SMILES: [I:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.Br[CH2:11][CH2:12][OH:13]>[OH-].[Na+]>[I:1][C:2]1[C:7]([O:8][CH2:11][CH2:12][OH:13])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1ccc(O)c(I)n1
Reactant: OCCBr
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(OCCO)c(I)n1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
2-Iodo-6-methyl-pyridin-3-ol (6.49 g, 27.6 mmol) was stirred in a 1M solution of sodium hydroxide (30 ml). To this was added 1-bromoethan-2-ol (3.91 ml, 55.20 mmol) dropwise at room temperature. The resulting solution was then heated to 100° C. and stirred for 2 hours. The reaction mixture was cooled and then extracted into chloroform (2×100 ml). The organic phases were combined and extracted with a solution of 1M sodium hydroxide (25 ml). The organic phase was then dried over magnesium sulfate and concentrated in vacuo. This provided the desired product which was used without further purification (5.26 g).
Reaction SMILES: [N+:1]([CH:4](O)[CH3:5])([O-:3])=[O:2].[C:7]([OH:10])(=[O:9])[CH3:8].C1C=CC=CC=1>OS(O)(=O)=O.O>[N+:1]([CH2:4][CH2:5][O:10][C:7](=[O:9])[CH3:8])([O-:3])=[O:2]
Reactant: CC(=O)O
Reactant: CC(O)[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: c1ccccc1
Product: CC(=O)OCC[N+](=O)[O-]

Procedure:
64 g nitroethanol, 50 ml glacial acetic acid, 250 ml benzene and 5 drops conc. H2SO4 were refluxed, using a water separator for 8 hours; 12 ml of H2O were collected. The solution was evaporated and vacuum distilled (1 mm at 60° C) yielding 89 g colorless nitroethylacetate.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][CH2:7][C:8]#[CH:9])[CH3:5])[CH3:2].C([Li])CCC.[OH:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:3][CH:4]([O:6][CH2:7][C:8]#[C:9][CH:20]([C:19]1[CH:22]=[CH:23][C:16]([OH:15])=[CH:17][CH:18]=1)[OH:21])[CH3:5])[CH3:2]
Reactant: O=Cc1ccc(O)cc1
Reactant: C#CCOC(C)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(C)OCC#CC(O)c1ccc(O)cc1
Reaction time: 0.5 h

Procedure:
A solution of 16 g (124.8 mmol) of 1-(1-ethoxyethoxy)-2-propyne in 270 ml of tetrahydrofuran was treated at -78° under argon with 78 ml of n-butyllithium (1.6 M in hexane). The mixture was stirred at -40° for 30 minutes and then a solution 7.62 g (62.4 mmol) of 4-hydroxybenzaldehyde in 53 ml of tetrahydrofuran was added within 10 minutes. The reaction mixture was warmed to 0°, stirred at 0° for a further 1 hour and then treated with 100 ml of saturated ammonium chloride solution. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed in succession with saturated sodium chloride solution and with water, dried over magnesium sulphate and concentrated. The residue was purified by flash chromatography on 600 g of silica gel (elution agent ether/hexane 1:1). There was obtained 4-(1-ethoxyethoxy)-(4-hydroxyphenyl)-2-butyn-1-ol as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])N=1.[Br-].[NH4+].CC(C)=[O:16]>O>[CH3:10][C:4]1([CH3:11])[NH:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2](=[O:16])[CH2:1]1
Reactant: CC(C)=O
Reactant: CC1=NC(C)(C)NC(C)(C)C1
Agent: [Br-]
Agent: [NH4+]
Solvent: O
Product: CC1(C)CC(=O)CC(C)(C)N1

Procedure:
5.0 g. of Acetonine and 3.2 g. of ammonium bromide were heated at 44°C. for 15 hours in a mixed solvent comprising acetone and water in various ratios as shown hereinbelow to effect the reaction. After completion of the reaction, the reaction mixture was purified in the same manner as in Example 5 to obtain triacetonamine in a yield as shown hereinbelow.
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.BrBr.[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([C@:16]([NH:38][C:39]([NH2:41])=[S:40])([C:24]2[CH:29]=[C:28]([O:30][C:31]([F:36])([F:35])[CH:32]([F:34])[F:33])[CH:27]=[C:26]([F:37])[CH:25]=2)[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:14][CH:15]=1>CCO>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([C@:16]([NH:38][C:39]2[S:40][C:1]3[CH2:5][CH2:4][CH2:3][C:2]=3[N:41]=2)([C:24]2[CH:29]=[C:28]([O:30][C:31]([F:35])([F:36])[CH:32]([F:33])[F:34])[CH:27]=[C:26]([F:37])[CH:25]=2)[CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[N:14][CH:15]=1
Reactant: O=C1CCCC1
Reactant: NC(=S)N[C@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(Cl)cn1
Agent: BrBr
Solvent: CCO
Product: Fc1cc(OC(F)(F)C(F)F)cc([C@@](Cc2ccccc2)(Nc2nc3c(s2)CCC3)c2ccc(Cl)cn2)c1
Temperature: 75 °C
Reaction time: 0.08 h
Yield: 26.5 %

Procedure:
To a solution of cyclopentanone (68 mg, 0.8 mmol) in EtOH (1 ml) was added Br2 (15 mg, 0.09 mmol) at r.t., sealed and stirred for 5 mins. The yellow solution became clear colorless. (R)-1-(1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)thiourea (20 mg, 0.04 mmol) was added to the reaction mixture and the mixture was heated at 75° C. for 16 hrs, then heated at 160° C. under microwave for 30 mins. The reaction mixture was purified by prep HPLC, desired fraction condensed under vacuum to give (R)-N-(1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-5,6-dihydro-4H-cyclopenta[d]thiazol-2-amine (6 mg, 27% yield). LCMS: 3.67 min [M+1] 566.40 (4 min gradient, MeOH/H2O 0.1% TFA); 1H NMR (400 MHz, CD3OD) δ ppm 2.32-2.42 (m, 2H), 2.55-2.66 (m, 2H), 2.69-2.80 (m, 2H), 3.88 (d, J=13.14 Hz, 1H), 4.28 (d, J=13.39 Hz, 1H), 6.27 (t, J=50.0 Hz, 1H), 6.61 (d, J=6.82 Hz, 2H), 6.97-7.09 (m, 4H), 7.24 (s, 1H) 7.34 (ddd, J=9.98, 2.02, 1.89 Hz, 1H), 7.41 (d, J=8.59 Hz, 1H) 7.79 (dd, J=8.59, 2.53 Hz, 1H), 8.38 (d, J=2.02 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:22])([CH2:19][CH:20]=[CH2:21])[C:3]([NH:5][N:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1)=[O:4].FC(F)(F)C(O)=O>ClCCl>[F:22][C:2]([F:1])([CH2:19][CH:20]=[CH2:21])[C:3]([NH:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:4]
Reactant: C=CCC(F)(F)C(=O)NN1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCC(F)(F)C(=O)NN1CCNCC1

Procedure:
A solution of 4-(2,2-difluoropent-4-enamido)-1-(t-butoxycarbonyl)piperazine (Example 16, step b) (5.0 g, 16.4 mmol) in 10 ml dichloromethane was treated with 2 ml trifluoroacetic acid. The reaction was concentrated after 24 hours, basified to pH 9 using 4N sodium hydroxide and extracted into dichloromethane. The organic extracts were dried (MgSO4) and concentrated to give 4-(2,2-difluoropent-4-enamido)piperazine as a yellow oil. δH (250 MHz, CDCl3) 2.83-3.01 (6H, m), 3.59-3.63 (2H, t, J=10 Hz), 3.67-3.71 (2H, t, J=10 Hz), 5.23 (1H, s), 5.27-5.30 (1H, d, J=7.5 Hz), 5.79-5.95 (1H, m).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:27]([O:29]C)=[O:28])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[N:18]([CH3:26])[CH2:17][CH2:16][CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br>C(Cl)Cl>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:27]([OH:29])=[O:28])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[N:18]([CH3:26])[CH2:17][CH2:16][CH2:15]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCCN(C)c1ccccc1-3
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CN1CCCn2c(c(C3CCCCC3)c3ccc(C(=O)O)cc32)-c2ccccc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 60 %

Procedure:
To a solution of methyl 14-cyclohexyl-5-methyl-5,6,7,8-tetrahydroindolo[1,2-e][1,5]benzodiazocine-11-carboxylate in DCM (0.1 M), 5 eq of BBr3 (1 M sol. in DCM) were added. The solution was stirred at RT for 20 mins. The solvent was evaporated in vacuo. The crude was then purified by automated prep RP-HPLC (stationary phase: column Waters XTERRA prep. C18, 5 um, 19×100 mm. Mobile phase: MeCN/H2O buffered with 0.1% TFA). Fractions containing the pure compound were combined and freeze dried to afford the title compound (60% over two steps).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:4]=[C:5]([C:8]([OH:10])=[O:9])[S:6][CH:7]=1.O=S(Cl)Cl.[CH3:17][CH2:18]O>>[CH2:17]([O:9][C:8]([C:5]1[S:6][CH:7]=[C:3]([C:2]([F:1])([F:11])[F:12])[N:4]=1)=[O:10])[CH3:18]
Reactant: O=C(O)c1nc(C(F)(F)F)cs1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1nc(C(F)(F)F)cs1
Temperature: 40 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a stirred solution of 4-trifluoromethylthiazole-2-carboxylic acid (98 g, 1 eq.) in EtOH (600 mL) was added dropwise SOCl2 (36 mL, 1 eq.). The mixture was stirred at 40° C. for 8 hrs and then at room temperature for 16 hrs. The reaction mixture was concentrated under reduced pressure and the residue was redissolved in DCM. Organics were washed with saturated aqueous NaHCO3 solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to yield compound 281 as a brown solid in 96% yield. 1H NMR (CDCl3, 400 MHz) δ 1.45 (t, J=7.14 Hz, 3H), 4.49-4.54 (q, J=7.10 Hz, 2H), 8.02 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[Li+].CC([N-]C(C)C)C.CCCCCCC.C1COCC1.C(C1C=CC=CC=1)C.[CH:37]([Si:40](Cl)([CH:44]([CH3:46])[CH3:45])[CH:41]([CH3:43])[CH3:42])([CH3:39])[CH3:38]>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[Si:40]([CH:44]([CH3:46])[CH3:45])([CH:41]([CH3:43])[CH3:42])[CH:37]([CH3:39])[CH3:38]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: COc1ccncc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: CCc1ccccc1
Solvent: CCCCCCC
Product: COc1ccncc1[Si](C(C)C)(C(C)C)C(C)C
Temperature: -25 °C
Reaction time: 0.5 h
Yield: 22.2 %

Procedure:
To a solution of 4-methoxypyridine (14.0 g, 128.3 mmol) in THF (150 mL) was added at −25° C., 2.0M LDA in heptane/THF/ethyl benzene (76.9 mL, 153.9 mmol). The mixture was stirred at −25° C. for 30 minutes. Triisopropylsilyl chloride (35.3 mL, 166.8 mmol) was added and the mixture was stirred at −25° C. for 15 minutes and then at room temperature for 16 hours. Water was added and the mixture was extracted with EtOAc. The extract was washed with water, brine dried over MgSO4 and concentrated to dryness. Purification of the residue by flash chromatography (hexane/ethylacetate 8:2-1:1) gave 4-methoxy-3-triisopropylsilanyl-pyridine (7.56 g, 22%) as an orange solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:14][CH2:15][CH2:16][CH:17]([CH2:23][CH:24]=[CH2:25])[C:18](OCC)=[O:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.[OH-].[Na+]>CCOCC>[CH2:7]([O:14][CH2:15][CH2:16][CH:17]([CH2:23][CH:24]=[CH2:25])[CH2:18][OH:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C=CCC(CCOCc1ccccc1)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: C=CCC(CO)CCOCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 1 M solution of lithium aluminium hydride (122 mL, 122 mmol) was added via cannula to a stirred solution of crude ester 11 (44 g), prepared according to Example 10, in dry ether (150 mL). The mixture was stirred for 2 h at room temperature under nitrogen, cooled to 0° C. and water (9 mL) was added dropwise with stirring, followed by 15% NaOH (9 mL) and water (27 mL), which was added dropwise at 0° C. to produce a white precipitate. The precipitate was filtered and washed with ether (2×50 mL). The filtrate was dried over MgSO4. The residue, obtained upon concentration, was subjected to column chromatography on silica gel. Contaminant benzyloxy-2-ethoxy ethanol (12.4 g) was first eluted with ether/hexane (2:1) while the alcohol 12(24 g, 59% based on diethyl allylmalonate) was eluted with 2% methanol in ether. IR (KBr) νmax 3404, 3071, 3033, 2930, 2868, 1640, 1498, 1454, 1361, 1202, 1100, 1042, 996, 916, 838, 697 cm−1; 1HNMR (CDCl3) δ 1.63-1.73 (m, 3 H), 2.02-2.15 (m, 2 H), 2.84 (t, J=5.8 Hz, 1 H), 3.45-3.58 (m, 4 H), 4.49 (s, 2 H), 5.00-5.03 (m, 2 H), 5.70-5.85 (m, 1 H), 7.26-7.35 (m, 5 H); 13CNMR (CDCl3) δ 31.65, 3620, 3891, 53.36, 65.58, 68.66, 73.13, 116.28, 127.69, 127.71, 128.39, 136.75, 137.88: mass spectrum (EI), m/z (rel intensity) 263 (M++1.10), 203 (1.5), 185 (2.3), 181 (3.5), 143 (2.5), 129 (5), 111 (6), 108 (6), 107 (22), 95 (5), 93 (6), 92 (12), 91 (100), 81 (16), 79 (10), 77 (5), 67 (10), 65 (13).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[CH:13]([CH3:18])[CH2:14][CH2:15][CH:16](Br)[C:9]2=[N:8][CH:7]=1)=[O:5])[CH3:2].[CH3:19][NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[CH:13]([CH3:18])[CH2:14][CH:15]=[C:16]([N:20]([CH3:19])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:9]2=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2n(c1=O)C(C)CCC2Br
Reactant: CNc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1cnc2n(c1=O)C(C)CC=C2N(C)c1ccccc1
Reaction time: 8 h
Yield: 25.9 %

Procedure:
10.0 g. (31.83 mmoles) of 9-bromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid ethyl ester are dissolved in 100 ml. anhydrous ethanol. 6.9 ml. (63.66 mmoles) of N-methylaniline are added to the solution, whereafter the reaction mixture is boiled under reflux for 8 hours. When the reaction is completed the solvent is distilled off at reduced pressure. To the residue 100 cm3 5% by weight aqueous solution of hydrochloric acid is added followed by extraction of the product twice with 30 ml. chloroform. The combined organic layers are dried above calcinated sodium sulfate and evaporated in vacuo. The residue is dissolved in 25 cm3 of methanol and allowed to stand overnight in a refrigerator. The precipitated crystals are filtered and washed with some methanol. 2.8 g. (25.9%) of 9-(N-methyl-anilino)-6-methyl-4-oxo-6,7-dihydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid ethyl ester is obtained which after recrystallization from methanol melts at 131°-133° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])=[C:10]([C:24]#[C:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:9]=1)(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[N:9]=[C:10]([C:24]#[C:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:11]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(NS(=O)(=O)c2ccccc2)c(C#Cc2ccccc2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(NS(=O)(=O)c2ccccc2)c(C#Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl-N-[5-(benzenesulfonamido)-6-(2-phenylethynyl)pyridin-2-yl]-carbamate C5a (37 mg, 0.08 mmol) and DCM:TFA (9:1, 4 ml) is stirred at RT for 2 h. The mixture is diluted with DCM and extracted with a saturated aqueous solution of NaHCO3. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The crude D5a (27 mg) is used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[C:5]([C:15]([O:17]CC(Cl)(Cl)Cl)=[O:16])=[CH:4][C:3]=1[S:23]([NH:26][CH2:27][O:28][C:29](=[O:54])[CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][N:38]([C:50]([CH3:53])([CH3:52])[CH3:51])[CH:39]([CH3:49])[C:40]([C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[CH:43]=1)=[O:41])=[O:35])(=[O:25])=[O:24]>C(O)(=O)C.[Zn]>[C:15]([C:5]1[C:6]([NH:8][CH2:9][C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[CH:7][C:2]([Cl:1])=[C:3]([S:23]([NH:26][CH2:27][O:28][C:29](=[O:54])[CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][N:38]([C:50]([CH3:51])([CH3:53])[CH3:52])[CH:39]([CH3:49])[C:40]([C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[CH:43]=2)=[O:41])=[O:35])(=[O:24])=[O:25])[CH:4]=1)([OH:17])=[O:16]
Reactant: CC(C(=O)c1cccc(Cl)c1)N(COC(=O)CCCCC(=O)OCNS(=O)(=O)c1cc(C(=O)OCC(Cl)(Cl)Cl)c(NCc2ccco2)cc1Cl)C(C)(C)C
Agent: [Zn]
Solvent: CC(=O)O
Product: CC(C(=O)c1cccc(Cl)c1)N(COC(=O)CCCCC(=O)OCNS(=O)(=O)c1cc(C(=O)O)c(NCc2ccco2)cc1Cl)C(C)(C)C

Procedure:
A solution of 2-[(6-(2-chloro-4-[(2-furanylmethyl)amino]-5-(2,2,2-trichloroethoxycarbonyl)phenylsulfonamidomethoxy)(6-oxo)hexanoyloxymethyl)(1,1-dimethylethyl)amino]-1-(3-chlorophenyl)-1-propanone (0.060 mole) in acetic acid (100 mL) is cooled in an ice water bath. Zinc dust (0.12 mole) is added in several portions with stirring, and the reaction is stirred for 2.5 hours at 0° C. The mixture is filtered to remove zinc salts, and the volatiles are removed by spin evaporation in vacuo. The residue is dissolved in cold water, and the solution is washed with diethyl ether. The aqueous solution is cooled in an ice bath and acidified by dropwise addition of 1.0 N hydrochloric acid solution (60 mL). The resulting solid may be collected and recrystallized to give 2-[(6-(5-carboxy-2-chloro-4-[(2-furanylmethyl)amino]phenylsulfonamidomethoxy)(6-oxo)hexanoyloxymethyl)(1,1-dimethylethyl)amino]-1-(3-chlorophenyl)-1-propanone (1220). See Greene et al., Protective Groups in Organic Synthesis, Second Edition, (1991) p. 240.