Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[CH2:2][N:3]=[C:4]=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.O.[NH:24]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C@H:25]([C:29](O)=[O:30])[CH:26]([CH3:28])[CH3:27].CNC.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[C:35]([O:34][C:32](=[O:33])[NH:24][C@@H:25]([CH:26]([CH3:28])[CH3:27])[C:29]([N:3]([CH3:4])[CH3:2])=[O:30])([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)C
Reaction time: 0.08 h

Procedure:
EDC.HCl (4.22 g, 22.0 mmol), reagent grade CH2Cl2 (80 mL), HOBt.H2O (3.36 g, 22.0 mmol), and Boc-Val-OH (4.34 g, 20.0 mmol) are added successively at 22° C. under air to a 250 mL round bottom flask equipped with a stir bar. The light yellow solution is allowed to stir for five minutes and dimethylamine (40 wt % in H2O, 5.3 mL, 50 mmol) is added drop-wise over one minute. The flask with the resulting light yellow solution is sealed with a rubber septum and allowed to stir for 12 h at 22° C. An aqueous solution of citric acid (10 wt %, 80 mL) is then added and the mixture is allowed to stir for 0.5 h during which time a white precipitate is formed. The precipitate is removed by filtration and the resulting two layers are separated. The organic layer is washed sequentially with an aqueous solution of citric acid (10 wt %, 80 mL), a saturated aqueous solution of NaHCO3 (80 mL), and brine (80 mL) and is dried over Na2SO4 to give (S)-tert-butyl(1-(dimethylamino)-3-methyl-1-oxobutan-2-yl)carbamate (S2) as pale yellow oil, which is employed without purification in the subsequent deprotection.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([Cl:39])[C:8]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[N:21]=[C:20]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][C@H:32]4[CH3:37])[N:19]=3)[CH:14]([CH3:38])[CH2:13]2)=[N:9][C:10]=1N)=[O:4].[Br:40]Br.N([O-])=O.[Na+]>Br.C(O)(=O)C.O>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([Cl:39])[C:8]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[N:21]=[C:20]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][C@H:32]4[CH3:37])[N:19]=3)[CH:14]([CH3:38])[CH2:13]2)=[N:9][C:10]=1[Br:40])=[O:4]
Reactant: BrBr
Reactant: COC(=O)c1nc(Cl)c(N2CCN(c3cc(-c4ccc(F)cc4)nc(N4CCOC[C@H]4C)n3)C(C)C2)nc1N
Agent: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1nc(Cl)c(N2CCN(c3cc(-c4ccc(F)cc4)nc(N4CCOC[C@H]4C)n3)C(C)C2)nc1Br
Temperature: 5 °C

Procedure:
To a cooled (5° C.) and well stirred mixture of 6′-amino-3′-chloro-4-[6-(4-fluoro-phenyl)-2-(3-(R)-methyl-morpholin-4-yl)-pyrimidin-4-yl]-3-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid methyl ester (10 g) in 48% HBr (75 mL) and glacial acetic acid (120 mL), add a solution (16 mL) of bromine in acetic acid (6:1) over a period of 45 min. To this mixture add a solution of NaNO2 (8.3 g) in water (18 mL) while maintaining the temperature below 8° C. After the addition is complete, stir the mixture for 30 min and then destroy the excess bromine by adding 100 mL of 30% NaHSO3. Neutralize the solution to pH 8 by the dropwise addition of 20% NaOH and then extract with EtOAc. Wash the organic extracts with dilute NH4OH, dry (Na2SO4) and concentrate under reduced pressure to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH:15]1([C:18](=[S:20])[NH2:19])[CH2:17][CH2:16]1>>[CH3:1][O:2][C:3]([C:4]1[N:19]=[C:18]([CH:15]2[CH2:17][CH2:16]2)[S:20][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:14]
Reactant: COC(=O)C(=O)C(Cl)c1ccccc1
Reactant: NC(=S)C1CC1
Product: COC(=O)c1nc(C2CC2)sc1-c1ccccc1

Procedure:
prepared by reaction of 3-chloro-2-oxo-3-phenyl-propionic acid methyl ester with cyclopropanecarbothioic acid amide. LC-MS: tR=0.99 min; [M+H]+=260.5.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:18][C:19]1[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:21][CH:20]=1.N1C=CC=CC=1.O>ClCCl>[F:1][C:2]1[CH:10]=[C:9]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:3]=1[C:4]([NH:18][C:19]1[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])=[CH:21][CH:20]=1)=[O:5]
Reactant: O=C(Cl)c1ccc(C(F)(F)C(F)(F)F)cc1F
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(NC(=O)c2ccc(C(F)(F)C(F)(F)F)cc2F)cc1
Temperature: 25 °C
Yield: 97.3 %

Procedure:
A solution of 2-fluoro-4-(1,1,2,2,2-pentafluoroethyl)benzoyl chloride (0.46 g, 1.66 mmol) in dichloromethane (6.34 mL) was added dropwise to a mixture of tert-butyl 4-aminobenzoate (321.4 mg, 1.66 mmol), pyridine (403.5 μL, 4.99 mmol) and dichloromethane (4.2 mL) at 0° C. The reaction was stirred and allowed to warm up to room temperature over 18 hours. To this reaction, water (5 mL) was added. The two layers were separated. The organic layer was washed with water (2×10 mL), dried over Na2SO4, filtered and evaporated under reduced pressure to yield tert-butyl 4-[[2-fluoro-4-(1,1,2,2,2-pentafluoroethyl)benzoyl]amino]benzoate (0.7 g, 97%) that was used in the next step without further purification. ESI-MS m/z calc. 433.11. found 434.3 (M+1)+; Retention time: 2.27 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 7.99-7.90 (m, 3H), 7.90-7.80 (m, 3H), 7.71 (dd, J=8.1, 1.7 Hz, 1H), 1.55 (s, 9H) ppm.
Reaction SMILES: C[N:2]([C:8](OC(C)(C)C)=O)[CH:3]([CH3:7])[C:4]([OH:6])=O.C1(N=C=NC2CCCCC2)CCCCC1.[C:30]1([C:36]#[C:37][C:38]2[N:43]=[C:42]([NH2:44])[CH:41]=[C:40]([C:45]([F:48])([F:47])[F:46])[CH:39]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN1C(=O)CCC1>[CH3:8][NH:2][CH:3]([CH3:7])[C:4]([NH:44][C:42]1[CH:41]=[C:40]([C:45]([F:47])([F:46])[F:48])[CH:39]=[C:38]([C:37]#[C:36][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:43]=1)=[O:6]
Reactant: Nc1cc(C(F)(F)F)cc(C#Cc2ccccc2)n1
Reactant: CC(C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(C)C(=O)Nc1cc(C(F)(F)F)cc(C#Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]propanoic acid (620 mg, 3.05 mmol) and N,N′-dicyclohexylcarbodiimide (315 mg, 1.53 mmol) in DCM (4 ml) is stirred at RT for 30 minutes. This mixture is added to 6-(2-phenylethynyl)-4-(trifluoromethyl)pyridin-2-amine B3b (100 mg, 0.38 mmol) and DIPEA (73 μl; 0.42 mmol) in NMP (5 ml). After stirring for 6 days at 50° C. the reaction mixture is concentrated in vacuo and the boc-protected product purified by NP chromatography. The boc-protected product is treated with DCM:TFA (9:1, 4 ml) for 1.5 h at RT. This 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 product is purified by RP HPLC. Yield: 10.2 mg (8%). HPLC-MS: M+H=348; tR=1.46 (*Method—1).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH:9]=[C:10]1[CH:15]=[CH:14][N:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]=[CH:11]1.[C:22]1([N:28]=[C:29]=[S:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC(C)=O>[C:16]1([N:13]2[CH:14]=[CH:15][C:10](=[N:9][C:29](=[S:30])[NH:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:11]=[N:12]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: S=C=Nc1ccccc1
Reactant: N=c1ccn(-c2ccccc2)nc1
Agent: Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: S=C(N=c1ccn(-c2ccccc2)nc1)Nc1ccccc1
Yield: 40.6 %

Procedure:
5.3 g (52.4 millimoles) of triethylamine were added dropwise to 10.0 g (48.2 millimoles) of 1,4-dihydro-4-imino-1-phenylpyridazine hydrochloride in 20 ml (22.6 g, 167 millimoles) of phenyl isothiocyanate at room temperature, while stirring. After the addition was complete, the reaction mixture was stirred for a further 2 hours at room temperature and then diluted with 30 ml of acetone. The product was filtered off under suction, washed with acetone, with water and again with acetone, and recrystallized from ethanol. 6.0 g (41% of theory) of 1,4-dihydro-1-phenyl-4-[(phenylthiocarbamyl)-imino]-pyridazine were isolated as orange crystals of melting point 171°-173° C.
Reaction SMILES: [CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([OH:22])=[C:11]4[O:12][C@H:13]5[C:14]([O:20]C)=[CH:15][CH:16]=[C:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1.OO.CC([OH:28])C>C(O)=O.[Pd]>[CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3=[CH:8][CH:9]=[C:10]([OH:22])[C:11]4[O:12][C@H:13]5[C:14]([CH2:15][CH2:16][C@:17]2([OH:28])[C@:5]5([C:6]=43)[CH2:4][CH2:3]1)=[O:20]
Reactant: COC1=CC=C2[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3C)[C@H]1O5
Reactant: CC(C)O
Agent: [Pd]
Agent: OO
Solvent: O=CO
Product: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@@]3(O)[C@H]1C5
Reaction time: 16 h

Procedure:
Oripavine (64 g, 0.215 mol) was dissolved in formic acid (98-100%, 120 g) and hydrogen peroxide (30% in water, 24.5 g, 0.216 mol) added at 0° C. The mixture was pumped continuously at 2 ml/min through a 30 ml continuous flow reactor at 80° C. (15 min residence time). An analytical control after the continuous reactor showed less than 1% Oripavine remaining. The continuous stream was added directly to the hydrogenation autoclave that was precharged with 2-propanol (204 g), formic acid (98-100%, 64 g) and 5% Pd/C (7.6 g) and held at 100° C. under H2 (40 bar). The hydrogenation was stirred for 16 h. After the hydrogenation, the catalyst was filtered off and the crude mixture was either basified with NaOH to obtain the low impurity Oxymorphone base, or treated with HCl in 2-Propanol to give the Oxymorphone HCl. The yield was 82% for the base.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:14]=[N:15][C:16]([CH:20]3[CH2:22][CH2:21]3)=[C:17]([Cl:19])[CH:18]=2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CCN=C=NCCCN(C)C.Cl.[CH:35]1([S:38]([NH2:41])(=[O:40])=[O:39])[CH2:37][CH2:36]1.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.ClCCl.CN(C)C=O>[Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:14]=[N:15][C:16]([CH:20]3[CH2:22][CH2:21]3)=[C:17]([Cl:19])[CH:18]=2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:41][S:38]([CH:35]1[CH2:37][CH2:36]1)(=[O:40])=[O:39])=[O:9]
Reactant: O=C(O)c1cc(Cl)c(Oc2cnc(C3CC3)c(Cl)c2)cc1F
Reactant: NS(=O)(=O)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NS(=O)(=O)C1CC1)c1cc(Cl)c(Oc2cnc(C3CC3)c(Cl)c2)cc1F
Reaction time: 0.33 h
Yield: 21.9 %

Procedure:
5-chloro-4-(5-chloro-6-cyclopropylpyridin-3-yloxy)-2-fluorobenzoic acid (Preparation 265, 15 mg, 0.44 mmol), 4-dimethylaminopyridine (81 mg, 0.66 mmol), and N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (127 mg, 0.66 mmol) were suspended in dichloromethane (2.5 mL). The reaction mixture was stirred for 20 minutes then dimethyl formamide (4 mL) was added and the suspension was stirred for 10 minutes. Cyclopropanesulfonamide (107 mg, 0.88 mmol) and N,N-diisopropylethylamine (160 μL, 0.88 mmol) were added and the reaction mixture was stirred for 18 hours at room temperature. The crude reaction mixture was purified by semi-preparative reverse phase HPLC (Column phenomenex Luna C18 150×21.2 mm 110 A 5μ, 3 injections of 2 ml, detection at 254 nm, fractions of 5 ml each, Gradient Solvent A: 0.05% HCO2H in acetonitrile, Solvent B: 0.05% HCO2H in water; 0 min 10% A, 2.5 min 10% A, 32.5 min 95% A, 37.5 min 95% A then return to initial conditions, flow rate 15 ml/min) to afford the title compound as a white solid (43 mg, 22%).
Reaction SMILES: [CH2:1]([C:4]1([OH:17])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].CN(C1C=CC=CN=1)C.[C:27](OC(=O)C)(=[O:29])[CH3:28].C(N(CC)CC)C>ClCCl>[C:27]([O:17][C:4]1([CH2:1][CH:2]=[CH2:3])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)(=[O:29])[CH3:28]
Reactant: C=CCC1(O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCC1(OC(C)=O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 20 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
A solution of tert-butyl 4-allyl-4-hydroxypiperidine-1-carboxylate (3.7 g, 14.51 mmol) in dichloromethane (20 mL) was treated with dimethylaminopyridine (1.8 g, 14.51 mmol), acetic anhydride (4.1 mL, 43.53 mmol) and triethylamine (6.1 mL, 43.53 mmol), and was stirred overnight at 20° C. The solvent was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. Combined organic extracts were washed with water, dried (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure, and purified by a standard method to provide the title compound 44B (3.4 g). LC-MS: m/z 284.4 (M+H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=O)[CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=2)=[CH:18][C:17]=1[CH3:34].Cl.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=2)=[CH:18][C:17]=1[CH3:34]
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)COc4cccc(C)c4)cc3C)c2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(NCCOc4cccc(C)c4)cc3C)c2cc1OC
Temperature: 0 °C
Yield: 79.9 %

Procedure:
N1-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-methylphenyl}-2-(3-methylphenoxy)acetamide (200 mg) was dissolved in tetrahydrofuran (10 ml) to prepare a solution. A 1 M solution (1.3 ml) of a borane-tetrahydrofuran complex in tetrahydrofuran was then added to the solution, and the mixture was stirred with heating under reflux for 2 hr. The reaction solution was cooled to 0° C. and was adjusted to pH=1 by the addition of 1 N hydrochloric acid, followed by stirring with heating under reflux for 30 min. The reaction solution was cooled to 0° C., was adjusted to pH=12 by the addition of a 1 N aqueous sodium hydroxide solution, and was extracted with chloroform. After the concentration of the extract, the residue was purified on a column using chloroform/methanol to give the title compound (155 mg, yield 80%).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.OC[C:8]1[C:13]([CH:14]([CH3:16])[CH3:15])=[CH:12][C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[C:21]1[CH:22]=[CH:23][C:24]([C:27]([NH:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:28])=[N:25][CH:26]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:5][CH2:1][C:8]1[C:13]([CH:14]([CH3:16])[CH3:15])=[CH:12][C:11]([C:17]([F:20])([F:18])[F:19])=[CH:10][C:9]=1[C:21]1[CH:22]=[CH:23][C:24]([C:27]([NH:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:28])=[N:25][CH:26]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)cc(C(C)C)c2CO)cn1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)cc(C(C)C)c2CBr)cn1
Temperature: 25 °C

Procedure:
Neat CBr4 (57 mg, 0.17 mmol) was added to a DCM solution (5 mL) of ethyl 3-(5-(2-(hydroxymethyl)-3-isopropyl-5-(trifluoromethyl)phenyl)picolinamido)propanoate (75 mg, 0.17 mmol) and PPh3 (45 mg, 0.17 mmol) and the resulting mixture was stirred at room temperature. After 16 h the resulting mixture was concentrated and purified via column chromatography to yield the title compound.
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:9]=[C:8]([C:10]([OH:12])=[O:11])[C:7]([NH:13]C(=O)C(C)(C)C)=[CH:6][N:5]=1)[CH3:3].Cl>>[NH2:13][C:7]1[C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:4]([N:2]([CH3:1])[CH3:3])=[N:5][CH:6]=1
Reactant: CN(C)c1cc(C(=O)O)c(NC(=O)C(C)(C)C)cn1
Agent: Cl
Product: CN(C)c1cc(C(=O)O)c(N)cn1
Yield: 98.8 %

Procedure:
2-(N,N-Dimethylamino)-5-(2,2-dimethylpropionamido)-pyridine-4-carboxylic acid (0.8 g) was treated with 5N HCl at reflux for 5 hours. The mixture was allowed to cool and evaporated to dryness to give the title compound (0.54 g); δH [2H6]DMSO 8.15(1H,s), 7.35(2H,bs), 6.70(1H,s), 3.10(6H,s), m/z (M+1+) 182.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13](=O)[C:12]3[CH:15]=[C:16]([O:19][C:20](=[O:26])[N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[CH:17]=[CH:18][C:11]=3[C:10]=2[O:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][N:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)=[CH:30][CH:29]=2)=[CH:5][CH:4]=1.CO.Cl.S([O-])([O-])(=O)=S.[Na+].[Na+]>CCCCCCC.COC(C)(C)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:13][C:12]3[CH:15]=[C:16]([O:19][C:20](=[O:26])[N:21]([CH2:22][CH3:23])[CH2:24][CH3:25])[CH:17]=[CH:18][C:11]=3[C:10]=2[O:27][C:28]2[CH:29]=[CH:30][C:31]([O:34][CH2:35][CH2:36][N:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)=[CH:32][CH:33]=2)=[CH:7][CH:8]=1
Reactant: CCN(CC)C(=O)Oc1ccc2c(c1)S(=O)C(c1ccc(OC)cc1)=C2Oc1ccc(OCCN2CCCCC2)cc1
Agent: Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Solvent: CCCCCCC
Solvent: COC(C)(C)C
Product: CCN(CC)C(=O)Oc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(OC)cc3)sc2c1
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
To a 500 mL flask (fitted with a stir bar) add diethyl-carbamic acid 2-(4-methoxy-phenyl)-1-oxo-3-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-1H-1Lambda*4*-benzo[b]thiophen-6-yl ester (8.46 mmoles; 5.00 g) and methanol (50.00 mL) at ambient temperature. To the resulting yellow slurry, add 36.5% hydrogen chloride (67.71 mmoles; 5.82 mL; 6.76 g) dropwise over 10 minutes to form a yellow solution. Then add solid sodium thiosulfate (25.39 mmoles; 4.06 g). Stir the resulting yellow mixture at 30° C. for 30 minutes and then quench with 100 mL of EtOAc and 200 mL of 0.5 N NaOH. Transfer the mixture to a separation funnel, separate the organic layer, and wash the organic layer with 100 mL of water and 50 mL of brine. Dry over sodium sulfate and concentrate which results in a thick oil. Dissolve the thick oil into 20 mL of t-butyl methyl ether (MTBE) and then add 50 mL of heptane. Stir the white slurry at room temperature overnight. Collect the white solid by filtration and wash with 50 mL of heptane. Dry in a vacuum oven at 50° C. for 5 hours and obtain 3.6 g of diethyl-carbamic acid 2-(4-methoxy-phenyl)-3-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-benzo[b]thiophen-6-yl ester as a white solid. MS: [M+H]: 575.2.
Reaction SMILES: N#N.[CH3:3][O:4][C:5](=[O:25])[CH:6]([NH:9][C:10](=[O:24])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2([CH3:23])[O:22][CH2:21][CH2:20][O:19]2)[CH:13]=1)[CH2:7]O.[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O>C1COCC1>[CH3:3][O:4][C:5]([CH:6]1[CH2:7][O:24][C:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3([CH3:23])[O:22][CH2:21][CH2:20][O:19]3)[CH:13]=2)=[N:9]1)=[O:25]
Reactant: COC(=O)C(CO)NC(=O)Cc1cccc(C2(C)OCCO2)c1
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: N#N
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)C1COC(Cc2cccc(C3(C)OCCO3)c2)=N1
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 3-hydroxy-2-{2-[3-(2-methyl-[1,3]dioxolan-2-yl)-phenyl]-acetylamino}-propionic acid methyl ester (2.30 g, 7.11 mmol) in dry THF (28.5 mL) was added at 0° C. to solution of (methoxycarbonylsulfamoyl)triethylammonium hydroxide (2.09 g, 8.50 mmol) in dry THF (28.5 mL) and the resulting suspension was stirred at 0° C. for 25 min. The reaction mixture was then stirred at reflux for 1 h. The mixture was then allowed to cool down to rt and filtered. The filter cake was rinsed with ether and EA and the filtrate was concentrated under reduced pressure. Purification of the residue by FC (7:3 EA-Hept) gave the title compound as a yellow oil. TLC: rf (7:3 EA-Hept)=0.34.
Reaction SMILES: [CH2:1]([O:5][CH:6]([C:9]1[C:10]([F:36])=[C:11]([C:15]2[N:16]=[C:17]([C:20]([C:22]3[CH:27]=[C:26]([F:28])[C:25]([CH:29]=[C:30]([CH3:34])[C:31]([OH:33])=[O:32])=[C:24]([F:35])[CH:23]=3)=[O:21])[S:18][CH:19]=2)[CH:12]=[CH:13][CH:14]=1)[CH2:7][CH3:8])[CH2:2][CH2:3][CH3:4].[OH-].[Na+:38]>CO>[Na+:38].[Na+:38].[CH2:1]([O:5][CH:6]([C:9]1[C:10]([F:36])=[C:11]([C:15]2[N:16]=[C:17]([C:20]([C:22]3[CH:23]=[C:24]([F:35])[C:25]([CH:29]=[C:30]([CH3:34])[C:31]([O-:33])=[O:32])=[C:26]([F:28])[CH:27]=3)=[O:21])[S:18][CH:19]=2)[CH:12]=[CH:13][CH:14]=1)[CH2:7][CH3:8])[CH2:2][CH2:3][CH3:4].[CH2:1]([O:5][CH:6]([C:9]1[C:10]([F:36])=[C:11]([C:15]2[N:16]=[C:17]([C:20]([C:22]3[CH:23]=[C:24]([F:35])[C:25]([CH:29]=[C:30]([CH3:34])[C:31]([O-:33])=[O:32])=[C:26]([F:28])[CH:27]=3)=[O:21])[S:18][CH:19]=2)[CH:12]=[CH:13][CH:14]=1)[CH2:7][CH3:8])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(CC)c1cccc(-c2csc(C(=O)c3cc(F)c(C=C(C)C(=O)O)c(F)c3)n2)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCOC(CC)c1cccc(-c2csc(C(=O)c3cc(F)c(C=C(C)C(=O)[O-])c(F)c3)n2)c1F
Reaction time: 1 h

Procedure:
To a suspension of methanol (100 mL) solution of 3-(4-{4-[3-(1-n-butyloxypropyl)-2-fluorophenyl]thiazol-2-ylcarbonyl}-2,6-difluorophenyl)-2-methylacrylic acid (3.22 mg) was added 2M sodium hydroxide aqueous solution (6.06 mL). After stirring for 1 h, n-hexylaldehyde (5.88 mL) was added to the reaction mixture. After methanol was evaporated under reduced pressure, the obtained residue was redissolved by adding water (40 mL). The water solution was freeze drying to obtain the compound (C1) 3.40 g.
Reaction SMILES: C([O:5][C:6]([CH2:8][N:9]1[C:13]2[CH:14]=[C:15]([I:18])[CH:16]=[CH:17][C:12]=2[N:11](C(OC(C)(C)C)=O)[C:10]1=[O:26])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[I:18][C:15]1[CH:16]=[CH:17][C:12]2[NH:11][C:10](=[O:26])[N:9]([CH2:8][C:6]([OH:7])=[O:5])[C:13]=2[CH:14]=1
Reactant: CC(C)(C)OC(=O)Cn1c(=O)n(C(=O)OC(C)(C)C)c2ccc(I)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cn1c(=O)[nH]c2ccc(I)cc21
Temperature: 25 °C

Procedure:
2.10 g (4.43 mmol) of tert-butyl 3-tert-butoxycarbonylmethyl-5-iodo-2-oxo-2,3-dihydrobenzimidazole-1-carboxylate (VIIj) were dissolved in dichloromethane (50 ml) and, while stirring at room temperature, trifluoroacetic acid (25 ml) was added. The reaction solution was stirred for 2 h and then the solvent and excess trifluoroacetic acid were removed in vacuo. The residue was taken up again in toluene, concentrated in vacuo and then dried in vacuo. Yield: 1.39 g (99%) of white solid.