Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]1([CH3:21])[C@@H:17]2[C@H:13]([CH2:14][O:15][CH2:16]2)[S:12](=[O:19])(=[O:18])[CH2:11][C:10]([NH2:20])=[N:9]1.FC(F)(F)C(O)=O.S(=O)(=O)(O)O.[N+:34]([O-])([OH:36])=[O:35].[OH-].[Na+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:34]([O-:36])=[O:35])=[CH:4][C:3]=1[C@:8]1([CH3:21])[C@@H:17]2[C@H:13]([CH2:14][O:15][CH2:16]2)[S:12](=[O:18])(=[O:19])[CH2:11][C:10]([NH2:20])=[N:9]1
Reactant: C[C@]1(c2ccccc2F)N=C(N)CS(=O)(=O)[C@H]2COC[C@@H]21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: C[C@]1(c2cc([N+](=O)[O-])ccc2F)N=C(N)CS(=O)(=O)[C@H]2COC[C@@H]21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of (3aR,8S,8aS)-rel-8-(2-fluoro-phenyl)-8-methyl-4,4-dioxo-3,3a,4,5,8,8a-hexahydro-1H-2-oxa-4λ6-thia-7-aza-azulen-6-ylamine (110 mg, 176 μmol) in trifluoroacetic acid (1.33 g, 11.7 mmol) was cooled to 0-5° C. Sulfuric acid (149 mg, 81.2 μl, 1.52 mmol), then nitric acid (12.1 mg, 8.01 μl, 192 μmol) was added slowly. The reaction mixture was stirred at 0° C. for 1 hour. In order to complete the reaction, another equivalent of nitric acid (12.1 mg, 8.01 μl, 192 μmol) was added and stirring continued at 0° C. for 2 hours. For the workup, ice-water was added to the reaction mixture, and the resulting suspension was set to pH ˜12 by addition of a solution of sodium hydroxide (32%). The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulphate and evaporated. The crude (3aR,8S,8aS)-rel-8-(2-fluoro-5-nitro-phenyl)-8-methyl-4,4-dioxo-3,3a,4,5,8,8a-hexahydro-1H-2-oxa-4λ6-thia-7-aza-azulen-6-ylamine was obtained as a brown solid and was engaged in the next step without purification. MS (ISP): m/z=358.3 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C([O:12][C:13](=[O:43])[CH2:14][N:15]([S:25]([C:28]1[CH:37]=[C:36]2[C:31]([C:32]([Cl:42])=[CH:33][N:34]=[C:35]2[NH:38][C:39]([NH2:41])=[NH:40])=[CH:30][CH:29]=1)(=[O:27])=[O:26])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])(C)(C)C>C(C(O)=O)(F)(F)F.C1(C)C=CC=CC=1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:42][C:32]1[C:31]2[C:36](=[CH:37][C:28]([S:25]([N:15]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])[CH2:14][C:13]([OH:43])=[O:12])(=[O:26])=[O:27])=[CH:29][CH:30]=2)[C:35]([NH:38][C:39]([NH2:41])=[NH:40])=[N:34][CH:33]=1
Reactant: COc1ccccc1CN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: COc1ccccc1CN(CC(=O)O)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 89.2 %

Procedure:
N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-(2-methoxybenzyl)glycine t-butyl ester trifluoroacetate (150 mg, 0.231 mmol) was dissolved in CF3CO2H (1.0 mL) and the mixture stirred at room temperature for 40 min. The mixture was diluted with PhMe, concentrated in vacuo, azeotroping with PhMe, and the residue triturated with i-Pr2O to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-(2-methoxybenzyl)glycine trifluoroacetate (122 mg, 0.206 mmol) as a white solid.
Reaction SMILES: P(=O)([O-])[O-].[S:5]1[CH:9]=[CH:8][C:7](CP(=O)(OCC)OCC)=[CH:6]1.O1C=CC=C1[CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28].FC1C=CC=CC=1CP(=O)(OCC)OCC.COC1C=C(C=C(OC)C=1OC)CP(=O)(OCC)OCC>>[S:5]1[CH:6]=[CH:7][CH:8]=[C:9]1[CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28]
Reactant: CCOP(=O)(Cc1ccsc1)OCC
Reactant: CCOP(=O)(Cc1ccco1)OCC
Agent: CCOP(=O)(Cc1cc(OC)c(OC)c(OC)c1)OCC
Agent: CCOP(=O)(Cc1ccccc1F)OCC
Agent: O=[PH]([O-])[O-]
Product: CCOP(=O)(Cc1cccs1)OCC

Procedure:
The following phosphonate reagents were also prepared by the above-described method: diethyl 3-thienylmethylphosphonate, diethyl 2-furanylmethylphosphonate, diethyl 2-fluorobenzylphosphonate, and diethyl 3,4,5-trimethoxybenzylphos-phonate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([NH:21][CH3:22])[CH3:20])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C:5]([Cl:8])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[CH:33][C:34]3[N:35]([CH:37]=[C:38]([NH:40][C:41](=[O:43])[CH3:42])[N:39]=3)[N:36]=2)O1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C(Cl)Cl.CO>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([C:31]2[CH:32]=[CH:33][C:34]3[N:35]([CH:37]=[C:38]([NH:40][C:41](=[O:43])[CH3:42])[N:39]=3)[N:36]=2)=[CH:3][C:4]=1[NH:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]([NH:21][CH3:22])[CH3:20])=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: CC(=O)Nc1cn2nc(B3OC(C)(C)C(C)(C)O3)ccc2n1
Reactant: CNC(C)c1ccc(S(=O)(=O)Nc2cc(Br)cnc2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: COCCOC
Solvent: CO
Product: CNC(C)c1ccc(S(=O)(=O)Nc2cc(-c3ccc4nc(NC(C)=O)cn4n3)cnc2Cl)cc1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 41.8 %

Procedure:
N-(5-bromo-2-chloropyridin-3-yl)-4-(1-(methylamino)ethyl)benzenesulfonamide (488 mg, 1.21 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazin-2-yl)acetamide (590.6 mg, 1.955 mmol), potassium carbonate (600 mg, 4.34 mmol), and Pd(dppf)Cl2*DCM complex (117.5 mg, 0.1439 mmol) were suspended in DME (8.0 mL) and water (2.0 mL). The reaction flask was fit with a reflux condensor and placed in a preheated oil bath (100 C) and stirred under nitrogen for 75 minutes. Then, the reaction was cooled to room temperature, and more N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazin-2-yl)acetamide (213 mg, 0.705 mmol) was added, and stirring was continued at 100 C. After another hour, the reaction was cooled to room temperature, diluted with DCM and MeOH, and filtered through a pad of Celite® (diatomaceous earth). The filtrate was concentrated and purified using silica gel on a filter (DCM to 50:1 to 20:1 to 5:1 to 3:1 DCM/2 N ammonia in MeOH). The fractions with product were collected, concentrated, treated with MeOH, and filtered. The solid was washed with MeOH, Et2O, DCM, MeOH, and Et2O. The solid was then collected and dried under high vacuum to afford N-(6-(6-chloro-5-(4-(1-(methylamino)ethyl)phenylsulfonamido)pyridin-3-yl)imidazo[1,2-b]pyridazin-2-yl)acetamide (253 mg, 42% yield) as a brown, amorphous solid. MS (ESI positive ion) m/z: 500 (M+1). Calcd for C22H22ClN7O3S: 499. 1H NMR (400 MHz, DMSO-d6): δ ppm 10.93 (s, 1H), 8.25 (s, 1H), 8.12-8.06 (m, 2H), 8.03 (d, J=9.54 Hz, 1H), 7.85 (d, J=8.53 Hz, 2H), 7.56-7.47 (m, 4H), 4.32-4.20 (m, 1H), 2.40 (s, 3H), 2.11 (s, 3H), 1.48 (d, J=6.53 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[C:7]2[NH:8][C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=[CH:4][C:3]=1[F:13].C([O-])([O-])=O.[Cs+].[Cs+].[Cl:20][CH2:21][CH2:22][CH2:23]I>>[Cl:20][CH2:21][CH2:22][CH2:23][N:8]1[C:7]2[C:2]([F:1])=[C:3]([F:13])[CH:4]=[CH:5][C:6]=2[O:11][CH2:10][C:9]1=[O:12]
Reactant: ClCCCI
Reactant: O=C1COc2ccc(F)c(F)c2N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C1COc2ccc(F)c(F)c2N1CCCCl
Yield: 72 %

Procedure:
5,6-Difluoro-4H-benzo[1,4]oxazin-3-one (0.13 g, 0.69 mmol), Cs2CO3 (0.45 g, 1.4 mmol), and 1-chloro-3-iodopropane (0.15 g, 0.76 mmol) were mixed according to GP2. Purified by column chromatography (SiO2; heptanes/EtOAc, gradient 0 to 30% EtOAc) to give the title compound (0.13 g, 75%). Rf=0.60 (heptanes/EtOAc 1:1); 1H NMR (CDCl3) d 6.88-6.74 (m, 2H), 4.52 (s, 2H), 4.19-4.14 (m, 2H), 3.58 (t, J=6.4 Hz, 2H), 2.22-2.14 (m, 2H); 13C NMR (CDCl3) d 165.1, 147.5 (dd, J=242.5 Hz, J=12.7 Hz), 143.8 (t, J=3.0 Hz), 140.7 (dd, J=249.8 Hz, J=17.3 Hz), 119.8 (d, J=4.6 Hz), 111.9 (dd, J=7.4 Hz, J=3.9 Hz), 111.2 (d, J=18.8 Hz), 68.4, 42.4 (d, J=9.7 Hz), 42.1, 31.1 (d, J=3.5 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][C:3]=1[O:13][CH3:14].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].O>CC(C)=O>[CH2:15]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][C:3]=1[O:13][CH3:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: COc1cc2c(cc1O)C(=O)CCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COc1cc2c(cc1OCc1ccccc1)C(=O)CCC2
Yield: 62.8 %

Procedure:
A mixture of 4.5 g (0.0233 mole) of 7-hydroxy-6-methoxy-1-tetralone, 5.4 g (0.032 mole) of benzyl bromide and 10 g (0.072 mole) of K2CO3 in 150 ml of acetone was heated to reflux overnight. The reaction as cooled, poured into water and extracted with EtOAc. The EtOAc was dried over Na2SO4 and evaporated to give 7 g of crude product. Crystallization with Et2O gave 4.13 g of product as a white solid, mp 110-111° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9].[C:12](=O)([O-:14])[O-:13].[K+].[K+].[C]=O>[Pd](Cl)Cl.C1(P(C(C(P(C2C=CC=CC=2)C2C=CC=CC=2)C)C)C2C=CC=CC=2)C=CC=CC=1.O>[F:9][C:8]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:12]([OH:14])=[O:13]
Reactant: FC(F)(F)c1ccccc1Cl
Reactant: O=C([O-])[O-]
Agent: Cl[Pd]Cl
Agent: CC(C(C)P(c1ccccc1)c1ccccc1)P(c1ccccc1)c1ccccc1
Agent: [C]=O
Solvent: O
Product: O=C(O)c1ccccc1C(F)(F)F
Temperature: 240 °C
Yield: 91.5 %

Procedure:
In an autoclave made of metal were placed 18 g of ortho-chlorobenzotrifluoride, 3.5 mg of palladium chloride, 170 mg of bisdiphenylphosphinobutane and 3.1 g of potassium carbonate. The air in the autoclave was replaced with carbon monoxide introduced thereinto in several times, after which carbon monoxide was further introduced to adjust its pressure therein to 30 kg/cm2. The reaction was carried out with stirring on a salt bath at a bath temperature of 240° C. After completion of the reaction, the reaction mixture was cooled to room temperature and water was added. The aqueous layer was separated and then acid was added thereto, followed by extraction from the aqueous layer. The ether layer was dried and then concentrated to obtain 3.9 g of ortho-trifluoromethylbenzoic acid.
Reaction SMILES: [CH3:1][C:2](C)([CH:4]=[CH2:5])[OH:3].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH:25]([Cl:28])([Cl:27])[Cl:26]>>[Cl:26][C:25]([Cl:28])([Cl:27])[CH2:5][CH2:4][CH:2]([OH:3])[CH3:1]
Reactant: C=CC(C)(C)O
Reactant: ClC(Cl)Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: CC(O)CCC(Cl)(Cl)Cl
Yield: 69 %

Procedure:
To a solution of 17.2 g of dimethyl vinyl carbinol in 150 ml of chloroform was added 0.8 g of benzoyl peroxide and, in an autoclave, the mixture was reacted at 135° C. and in a nitrogen atmosphere for 18 hours. Then, the unreacted dimethyl vinyl carbinol and chloroform were removed by distillation under reduced pressure. As the residue was obtained 30.1 g of a dark-reddish viscous fluid. This residue was subjected to vacuum distillation to obtain 28.2 g (yield 69%) of 1,1,1-trichloro-4-pentanol. Gas-chromatographic analysis of this product showed its purity to be 95.4%. mass spectrometric data suggested that the impurity comprised 1,1,3-trichloro-4-methyl-4-pentanol. The following procedures were used for structural identification of 1,1,1-trichloro-4-methyl-4-pentanol.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][C@H:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([OH:23])[CH2:12]1)=O)C1C=CC=CC=1>CO.[Pd]>[OH:23][C@@H:13]1[C@@H:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15][CH2:16][NH:11][CH2:12]1
Reactant: O=C(OCc1ccccc1)N1CC[C@H](c2ccccc2)[C@@H](O)C1
Agent: [Pd]
Solvent: CO
Product: O[C@H]1CNCC[C@@H]1c1ccccc1
Yield: 117.1 %

Procedure:
A solution of (3R*,4R*)-1-benzyloxycarbonyl-3-hydroxy-4-phenylpiperidine (0.3 g) in methanol (30 mL) was treated with 10% palladium on carbon (0.03 g) and hydrogenated at atmospheric pressure for 2 hours. The reaction mixture was filtered through diatomaceous earth and evaporated to afford (3R*,4R*)-3-hydroxy-4-phenylpiperidine (0.2 g); MS: m/z=178(M+1); NMR: 1.44-1.58 (m, 2), 2.23-2.5 (m, 9), 4.36 (broad, 1), 7.13-7.29 (m, 5).
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[CH:8][N:9]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:10](B(O)O)=[C:6]2[C:5](=[O:22])[N:4]([CH3:23])[C:3]1=[O:24].Br[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1>>[F:32][C:28]1[CH:27]=[C:26]([C:10]2[N:9]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:8]=[C:7]3[C:6]=2[C:5](=[O:22])[N:4]([CH3:23])[C:3](=[O:24])[N:2]3[CH3:1])[CH:31]=[CH:30][CH:29]=1
Reactant: Cn1c(=O)c2c(B(O)O)n(COCC[Si](C)(C)C)cc2n(C)c1=O
Reactant: Fc1cccc(Br)c1
Product: Cn1c(=O)c2c(-c3cccc(F)c3)n(COCC[Si](C)(C)C)cc2n(C)c1=O

Procedure:
The title compound was prepared from 1,3-dimethyl-2,4-dioxo-6-((2-(trimethylsilyl)ethoxy)methyl)-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-5-ylboronic acid (Example 9, step 2) and 1-bromo-3-fluorobenzene by a similar method to Example 9 step 3;
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][C:11]1[C:16]([OH:17])=[C:15]([F:18])[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:13]([CH3:25])[C:12]=1[C:26]#[N:27].[CH3:28][O:29][CH2:30][C:31](Cl)=[O:32].[Cl-].[NH4+]>C(OCC)(=O)C>[CH3:28][O:29][CH2:30][C:31]([O:17][C:16]1[C:15]([F:18])=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]([CH3:25])=[C:12]([C:26]#[N:27])[C:11]=1[NH2:10])=[O:32]
Reactant: Cc1c(C#N)c(N)c(O)c(F)c1-c1ccccc1
Reactant: COCC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COCC(=O)Oc1c(N)c(C#N)c(C)c(-c2ccccc2)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.5 %

Procedure:
Diisopropylethylamine (0.64 ml, 3.7 mmol) was added to an ethyl acetate (8 ml) solution of 4-amino-3-cyano-6-fluoro-5-hydroxy-2-methylbiphenyl (I-41) (180 mg, 0.74 mmol), then with cooling with ice, methoxyacetyl chloride (0.17 ml, 1.85 mmol) was added, followed by stirring for 16 hours with gradually heating up to room temperature. Aqueous saturated ammonium chloride solution was added to the reaction liquid, followed by extraction three times with ethyl acetate, the organic layer was washed with saturated sodium bicarbonate water and saturated brine, then dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the resulting residue was subjected to column chromatography, and the eluate with n-hexane:ethyl acetate (1:1) was concentrated under reduced pressure to obtain the entitled compound (229 mg, 99%) as a yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:40])[C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:12][CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=3)[N:16]([CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:15]=2[CH2:37][CH2:38][NH2:39])[CH3:11])=[CH:6][CH:5]=1.[C:41]1([CH2:47][S:48](Cl)(=[O:50])=[O:49])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[CH:24]([N:16]1[C:17]2[C:22](=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:14]([CH2:13][CH2:12][N:10]([CH3:11])[C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:2])=[O:40])=[CH:9][CH:8]=2)=[C:15]1[CH2:37][CH2:38][NH:39][S:48]([CH2:47][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)(=[O:50])=[O:49])([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC(=O)c1ccc(N(C)CCc2c(CCN)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Product: CN(CCc1c(CCNS(=O)(=O)Cc2ccccc2)n(C(c2ccccc2)c2ccccc2)c2ccc(Cl)cc12)c1ccc(C(=O)O)cc1
Yield: 83 %

Procedure:
The intermediate from step 7 was treated with α-toluenesulfonyl chloride according to the procedure in Example 87 step 2 to generate the desired product in 83% yield.
Reaction SMILES: O=[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8](F)[CH:7]=1)[CH2:3][C:4]#[N:5].[NH2:13][C:14]([NH2:16])=[S:15].II>N1C=CC=CC=1>[NH2:16][C:14]1[S:15][C:3]([C:4]#[N:5])=[C:2]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:13]=1
Reactant: NC(N)=S
Reactant: N#CCC(=O)c1cccc(F)c1
Agent: II
Solvent: c1ccncc1
Product: N#Cc1sc(N)nc1-c1ccccc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 102.3 %

Procedure:
5 g (34.0 mmol) of 3-oxo-3-(3-fluorophenyl)-propanenitrile were dissolved in pyridine (30 ml) and thiourea (5 g, 68.0 mmol) and iodine (8.70 g, 34.40 mmol) were added successively. The solution was stirred at 100° C. for 12 h. The mixture was then cooled to room temperature and poured into ice-water (500 ml). The resulting solid was filtered, washed with water and recrystallized from ethanol to give 7.0 g (91%) of a yellow solid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[N:10][C:3]=12.[H-].[Na+].[CH3:13][Si:14]([CH2:17][CH2:18][O:19][CH2:20]Cl)([CH3:16])[CH3:15]>CN(C=O)C>[I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:20][O:19][CH2:18][CH2:17][Si:14]([CH3:16])([CH3:15])[CH3:13])[CH:9]=[N:10][C:3]=12
Reactant: C[Si](C)(C)CCOCCl
Reactant: Ic1ccnc2[nH]cnc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cnc2c(I)ccnc21

Procedure:
850 mg (3.47 mmol) of 7-iodo-3H-imidazo[4,5-b]pyridine was dissolved in 3.5 mL DMF. 153 mg (3.82 mmol) of 60% sodium hydride was added followed by 670 μL (3.82 mmol) of trimethylsilylethoxymethyl chloride. Yield: 424 mg of an oily product, 90% pure.
Reaction SMILES: [OH-].[Na+].FC(F)(F)C([NH:7][C@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=O.CCO>>[NH2:7][C@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1NC(=O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1N
Reaction time: 8 h

Procedure:
Aqueous sodium hydroxide (50%, 10 g, 0.125 mole, 5.7 eq) was added to a solution of cis-tert-butyl 2-(2,2,2-trifluoroacetamido)cyclohexylcarbamate in EtOH (about 21.9 mmol). An exotherm from 20 to 37° C. was observed and a fine white slurry formed. The reaction mixture was stirred overnight, during which further solids precipitated out of solution. The solvent volume was concentrated under reduced pressure to about 10 to 15 mL and then IPAc (40 mL) and water (30 mL) were added to form a clean bi-phasic solution. Following phase separation the aqueous phase was extracted with IPAc (15 mL) and the organic extracts were combined and washed with water (15 mL) to give the title compound as a crude racemic product in IPAc.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[N:12]([CH2:13][C:14]2[C:22]([Cl:23])=[CH:21][C:17]3[O:18][CH2:19][O:20][C:16]=3[CH:15]=2)[C:11]([CH2:24][CH2:25][CH3:26])=[N:10][C:9]=1[CH:27]=O)=[O:7])[CH3:4]>[Cl-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[Cl:23][C:22]1[C:14]([CH2:13][N:12]2[C:8]([C:6]([O:5][CH2:3][CH3:4])=[O:7])=[C:9](/[CH:27]=[CH:13]/[C:14]3[CH:22]=[CH:21][CH:17]=[CH:16][CH:15]=3)[N:10]=[C:11]2[CH2:24][CH2:25][CH3:26])=[CH:15][C:16]2[O:20][CH2:19][O:18][C:17]=2[CH:21]=1
Reactant: CCCc1nc(C=O)c(C(=O)OCC)n1Cc1cc2c(cc1Cl)OCO2
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCc1nc(/C=C/c2ccccc2)c(C(=O)OCC)n1Cc1cc2c(cc1Cl)OCO2
Reaction time: 0.5 h
Yield: 153.9 %

Procedure:
150 mg of sodium hydride is added to a suspension containing 1.2 g of benzyltriphenyl phosphonium chloride in 30 ml of tetrahydrofuran. Agitation is carried out for 30 minutes, the reaction medium is cooled down to +10 C and 1 g of the aldehyde obtained in Example 44 in solution in tetrahydrofuran is added and agitation is continued for 2 hours at ambient temperature, followed by filtration, the organic phase is washed with tetrahydrofuran, the solvent is eliminated under reduced pressure and the residue is chromatographed on silica (eluant: CH2Cl2 -AcOEt 80-20). 920 mg of expected product is obtained. M.p.=161° C.
Reaction SMILES: [F:1][C@@H:2]1[CH2:6][N:5]([C:7](=[O:26])[CH2:8][C:9]2[CH:25]=[CH:24][C:12]3[N:13]=[C:14]([NH:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[CH3:23])[O:15][C:11]=3[CH:10]=2)[C@H:4]([CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36]C)=[O:35])[CH2:3]1.[OH-].[Na+:39].C(O)C.CCOCC>C1COCC1>[F:1][C@@H:2]1[CH2:6][N:5]([C:7](=[O:26])[CH2:8][C:9]2[CH:25]=[CH:24][C:12]3[N:13]=[C:14]([NH:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[CH3:23])[O:15][C:11]=3[CH:10]=2)[C@H:4]([CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O-:36])=[O:35])[CH2:3]1.[Na+:39]
Reactant: COC(=O)CCCCCOC[C@@H]1C[C@H](F)CN1C(=O)Cc1ccc2nc(Nc3ccccc3C)oc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccccc1Nc1nc2ccc(CC(=O)N3C[C@@H](F)C[C@H]3COCCCCCC(=O)[O-])cc2o1
Reaction time: 24 h

Procedure:
Methyl 6-((2S,4S)-4-fluoro-1-(2-(2-methylphenylamino)-6-benzoxazolylacetyl)-2-pyrrolidinylmethoxy)hexanoate (330 mg, 0.645 mmol) was dissolved in THF (30 ml). At room temperature, 0.25N NaOH (30 ml) was added and the mixture was stirred for 24 hours. The reaction mixture was distilled under reduced pressure to remove the solvent. The residue was acidified with 1N HCl, followed by extraction with a chloroform/methanol (10/1) mixture. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by thin-layer silica gel chromatography, followed by separation by using chloroform/methanol (20/1), whereby the title compound (238 mg, 74%) was obtained as a yellow oil. Ethanol (10 ml) and 1N NaOH (0.478 ml, 0.478 mmol) were added to the resulting carboxylic acid derivative (238 mg, 0.478 mmol). After stirring for 10 minutes, ether was added to crystallize the residue, which had been obtained by distilling off the solvent under reduced pressure, whereby sodium 6-((2S,4S)-4-fluoro-1-(2-(2-methylphenylamino)-6-benzoxazolylacetyl)-2-pyrrolidinylmethoxy)hexanoate (199 mg) was obtained.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([N:11]=[C:12]=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=[O:3])[CH3:2].Cl.[CH2:28]([NH2:31])[CH2:29][CH3:30].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>CC#N>[C:1]([O:4][C@H:5]1[C@H:10]([NH:11][C:12]([NH:31][CH2:28][CH2:29][CH3:30])=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N=C=S)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCCN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCNC(=S)N[C@H]1[C@H](OC(C)=O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 1 h
Yield: 87.2 %

Procedure:
To a stirred solution of (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-isothiocyanato-tetrahydro-2H-pyran-2,4,5-triyl triacetate (530 mg, 1.36 mmol) in CH3CN (7 mL) was added neat propylamine hydrochloride (260 mg, 2.72 mmol) followed by triethylamine (378 μL, 2.72 mmol) and the resulting mixture was stirred for 1 h. Saturated aqueous NaHCO3 (20 mL) was added, then the resulting mixture was extracted with CH2Cl2 (3×10 mL) and the combined organic extracts were dried (MgSO4) and concentrated. The resulting crude material was purified by flash chromatography on silica gel (hexane/EtOAc 1:1) to give (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-(3-propylthioureido)-tetrahydro-2H-pyran-2,4,5-triyl triacetate as a white foam (532 mg, 87% yield). 1H NMR (500 MHz, CDCl3) δ 0.97 (t, 3H, J=7.5 Hz), 1.59-1.64 (m, 2H), 1.53-1.59 (m, 2H), 2.06 (s, 3H), 2.08 (s, 3H), 2.12 (s, 3H), 2.15 (s, 3H), 3.35 (br s, 2H), 3.81-3.85 (m, 1H), 4.13-4.17 (m, 2H), 4.20-4.25 (m, 1H), 4.29 (dd, 1H, J=4.5, 12.5 Hz), 5.17-5.23 (m, 2H), 5.73 (d, 1H, J=8.5 Hz), 6.07 (br s, 1H).
Reaction SMILES: CI.[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[OH:13].[C:14]([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[O:13][CH3:14]
Reactant: O=[N+]([O-])c1cccc(F)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: COc1c(F)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
MeI (27.1 g, 191 mmol) was added dropwise to the suspension of 2-fluoro-6-nitrophenol (25.0 g, 159 mmol) and K2CO3 (44.0 g, 318 mmol) in 200 mL of DMF. The mixture was stirred overnight at 25° C. then warmed to 60° C. and stirred for 3 hours. The mixture was diluted with 1 L of EtOAc and washed with water (3×100 mL) and brine (100 mL), dried over anhydrous Na2SO4 and concentrated to afford the title compound.