Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH2:6]=[CH:7][CH2:8][CH:9]([OH:13])[CH2:10][CH:11]=[CH2:12].C1(C(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:33]1CCCC1>>[CH2:8]([C@@H:9]([OH:13])[CH2:10][C@@H:11]1[CH2:12][O:33]1)[CH:7]=[CH2:6]
Reactant: C1CCOC1
Reactant: C=CCC(O)CC=C
Agent: [Li]CCCC
Solvent: c1ccc(C(c2ccccc2)c2ccccc2)cc1
Product: C=CC[C@@H](O)C[C@@H]1CO1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium, 129 mL (200 mmol), is added dropwise to a 0° C. solution of 1,6-heptadien-4-ol, 22.4 g (0.2 mol), in 200 mL of anhydrous tetrahydrofuran until the triphenylmethane indicator turned red. Carbon dioxide is then bubbled in for 30 minutes (lecture bottle carbon dioxide passed through drierite) and the light yellow solution is stirred for 30 minutes under a balloon of carbon dioxide. To this solution is added iodine, 101.4 g (0.4 mol), dissolved in ~200 mL of anhydrous tetrahydrofuran over 60 minutes. The mixture is allowed to warm to room temperature overnight, diluted with ethyl acetate, washed with 10% sodium bisulfite solution, saturated solution of sodium bicarbonate, brine, and dried (magnesium sulfate). The crude product is dissolved in 200 mL of methanol and 20 mL of water, cooled to 0° C. and 0.5 g of solid potassium carbonate is added. The mixture is vigorously stirred for six hours, filtered, concentrated, and partitioned between ethyl acetate and brine. After extracting the aqueous layer 2× with ethyl acetate, the combined organics are washed with brine and dried (magnesium sulfate). Flash chromatography (4:1 hexane-ethyl acetate) provides, after concentration in vacuo, 18 g of (R*,R*)-α-2-propenyloxiraneethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[N:11][N:10]=2)=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:35]([O-:38])([O-])=[O:36].[K+].[K+].Cl.Cl[C:43]1[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=1>CN(C=O)C.CO>[F:22][C:21]([F:24])([F:23])[C:35]([OH:38])=[O:36].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:13][C:12]([C:14]3[CH:15]=[CH:16][C:17]([O:20][C:43]4[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=4)=[CH:18][CH:19]=3)=[N:11][N:10]=2)=[CH:4][C:3]=1[C:21]([F:22])([F:23])[F:24]
Reactant: O=C([O-])[O-]
Reactant: Clc1ccncc1
Reactant: Oc1ccc(-c2nnc(Nc3ccc(Cl)c(C(F)(F)F)c3)o2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: FC(F)(F)c1cc(Nc2nnc(-c3ccc(Oc4ccncc4)cc3)o2)ccc1Cl
Product: O=C(O)C(F)(F)F
Temperature: 80 °C

Procedure:
4-(5-{[4-chloro-3-(trifluoromethyl)-phenyl]amino}-1,3,4-oxadiazol-2-yl)phenol (100 mg, 0.281 mmol) was dissolved in ca. 2 mL of anhydrous DMF under argon. Solid potassium bis(trimethylsilyl)amide (225 mg, 1.12 mmol) was added and the resulting yellow solution was heated at 80° C. for 15 min. Then solid K2CO3 (38.8 mg, 0.281 mmol) was added, followed by 4-chloropyridine hydrochloride (84.3 mg, 0.562 mmol). The reaction mixture was microwaved at 200° C. for 25 min (Initiator, Biotage). Then it was diluted with 1 mL of MeOH, filtered through 0.22 um syringe filter and purified by preparative reverse-phase chromatography using acetonitrile/water gradient with 0.1% TFA. The major peak having the mass of the product was collected; solvent was removed in vacuo to give the title product as a white fluffy solid (85.6 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH:20][C:21]([NH:23][C:24]3[N:28]([C:29]4[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=4)[N:27]=[C:26]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH:25]=3)=[O:22])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1.C[N:41]=[C:42]=[O:43].N1C=CC=C[CH:45]=1>>[CH3:45][N:1]([C:2]1[CH:7]=[C:6]([CH2:8][O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH:20][C:21]([NH:23][C:24]3[N:28]([C:29]4[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=4)[N:27]=[C:26]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH:25]=3)=[O:22])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1)[C:42]([NH2:41])=[O:43]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccnc(N)c3)c3ccccc23)cc1
Reactant: CN=C=O
Reactant: c1ccncc1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccnc(N(C)C(N)=O)c3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 45 %

Procedure:
To a solution of 1-(4-((2-aminopyridin-4-yl)methoxy)naphthalen-1-yl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea (Intermediate A) (70 mg, 0.13 mmol) in anhydrous pyridine (1.5 mL) was added methyl isocyanate (14 μL, 0.24 mmol) and the mixture allowed to stir at RT for 72 hr. Pyridine was removed under vacuum and the residue triturated with DCM (3.0 mL). Filtration afforded an off-white powder, methyl 4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-ylurea (Example 2) (36 mg, 45%): m/z 578 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.27 (9H, s), 2.39 (3H, s), 2.74 (3H, d), 5.30 (2H, s), 6.36 (1H, s), 6.99 (1H, d), 7.05 (d, 1H), 7.35, (2H, d), 7.44 (2H, d), 7.54-7.64 (4H, m), 7.93 (1H, d), 8.19 (1H, d), 8.23 (1H, brs), 8.35 (1H, d), 8.58 (1H, s), 8.79 (1H, s), 9.36 (1H, s).
Reaction SMILES: [CH:1]1([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([CH3:24])=[CH:12][C:13](=[O:23])[N:14]3[CH2:17][CH:18]3OCC[O:19]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>O>[CH:1]1([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([CH3:24])=[CH:12][C:13](=[O:23])[N:14]3[CH2:17][CH:18]=[O:19])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1cc(=O)n(CC2OCCO2)c2cc(C3CCCCC3)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(=O)n(CC=O)c2cc(C3CCCCC3)ccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 0.31 g of 7-cyclohexyl-1-(1,3-dioxolan-2-ylmethyl)-4-methylquinolin-2(1H)-one, 10 mL of a 80% aqueous trifluoroacetic acid solution was added, the mixture was stirred at room temperature for 2 hours and then stood still at room temperature for 15 hours. Thereto were added ethyl acetate and water, and the reaction mixture was adjusted to pH 7.5 with an aqueous saturated sodium hydrogen carbonate solution. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed sequentially with water and an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 0.11 g of a colorless oily substance, (7-cyclohexyl-4-methyl-2-oxo-1,2-dihydroquinolin-1-yl)acetaldehyde.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.C[N:14]([CH3:18])[CH2:15][CH2:16][NH2:17].[CH2:19](N(CC)CC)C.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH3:18][N:14]([CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)[CH2:15][CH2:16][NH:17][CH3:19]
Reactant: CN(C)CCN
Reactant: CCN(CC)CC
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CNCCN(C)Cc1ccc(C(=O)OC)cc1
Yield: 62 %

Procedure:
A mixture of methyl 4-(bromomethyl)benzoate (2 g, 8.73 mmol) and N,N-dimethylethan-1,2-diamine (7.5 mL, 70 mmol) was heated with triethylamine (9.8 mL, 70 mmol) in tetrahydrofuran (80 mL) to reflux for two hours. After cooling, the mixture was treated with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Flash chromatography gave 1.28 g of methyl 4-[(methyl(2-(methylamino)ethyl)amino)methyl]benzoate, 1H NMR (300 MHz, CD3OD) δ 7.97 (d, 2H), 7.45 (d, 2H), 3.59 (s, 2H), 2.67 (m, 2H), 2.54 (m, 2H), 2.35 (s, 3H), 2.22 (s, 3H) ppm.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][NH:12]2)=[CH:8][CH:7]=1)([O-:5])=[O:4].[OH:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[C:19]#[N:20].I[CH2:25]I>CN(C=O)C>[N+:3]([C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][N:12]2[CH2:25][O:15][C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=2)[C:19]#[N:20])=[CH:8][CH:7]=1)([O-:5])=[O:4]
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Reactant: N#Cc1cccc(O)c1
Reactant: ICI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cccc(OCn2ccc3ccc([N+](=O)[O-])cc32)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 50.8 %

Procedure:
To a mixture of NaH (3.0 g, 75.0 mmol, 60%) in DMF (20 mL) were added a solution of 6-nitro-1H-indole (4.86 g, 30.0 mmol) in DMF (10 mL) and a solution of 3-hydroxybenzonitrile (3.57 g, 30.0 mmol) in DMF (10 mL) at 0° C. and the mixture was stirred at rt for 2 h. To the reaction mixture was added a solution of diiodomethane (7.5 mL, 90.0 mmol) in DMF (10 mL) slowly without light and the mixture was stirred at rt for 20 h. The mixture was then quenched with water and filtered. The filtrate was extracted with DCM (30 mL×6) and the combined organic layers were washed with brine (50 mL×3), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a yellow solid (4.47 g, 51%).
Reaction SMILES: C(OC(N1CCC[C@H]1/C=C(/[C:15]1[CH2:21][C@H:20]2N([C:18](=O)[C@@H:19]2[C@H:22]([OH:24])C)[C:16]=1[C:26](OCC=C)=O)\C)=O)C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC1(C)CC(=[O:58])CC(=O)C1>O1CCCC1.C(O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:18][C:19]([C:22]([OH:58])=[O:24])=[CH:20][CH2:21][CH2:15][CH2:16][CH3:26]
Reactant: C=CCOC(=O)C1=C(/C(C)=C/[C@@H]2CCCN2C(=O)OCC=C)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reactant: CC1(C)CC(=O)CC(=O)C1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCC=C(C)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 163.2 %

Procedure:
To a solution of allyl (5R,6S)-3-[(E)-2-{(2S)-1-allyloxycarbonylpyrrolidin-2-yl}-1-methylethenyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (2.82 g) in a mixture of tetrahydrofuran (28 ml) and ethanol (14 ml) were added successively triphenylphosphine (0.51 g), 5,5-dimethyl-1,3cyclohexanedione (dimedone) (1.79 g), and tetrakis-(triphenylphosphine) palladium (0) (220 mg). Stirring at ambient temperature for 1 hour gave a precipitate, which was collected by filtration, washed with tetrahydrofuran (40 ml) and dissolved in water (150 ml). The solution was washed with ethyl acetate (50 ml×2), concentrated in vacuo and lyophilized to give (5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-[(E)-2-(2S)-pyrrolidin-2-yl}-1-methylethenyl]-1-azabicyclo[b 3.2.0]hept-2-ene-2-carboxylic acid (1.52 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][NH:8][C:9](=[O:22])[C@@H:10]([NH:14]C(=O)OC(C)(C)C)[CH:11]([CH3:13])[CH3:12])=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:14][C@@H:10]([CH:11]([CH3:13])[CH3:12])[C:9]([NH:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:24][CH:23]=1)=[O:22]
Reactant: COc1ccc(CNC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CNC(=O)[C@@H](N)C(C)C)cc1
Temperature: 0 °C
Reaction time: 7 h
Yield: 73.1 %

Procedure:
A solution of (S)-tert-butyl 1-(4-methoxybenzylamino)-3-methyl-1-oxobutan-2-ylcarbamate (1.50 g, 4.46 mmol) in dichloromethane (15 mL) was cooled to 0° C. Trifluoroacetic acid (2 mL) was added and the mixture stirred at 0° C. for 7 hours. The reaction mixture was concentrated and the residue taken up in dichloromethane and washed with saturated aqueous NaHCO3 solution. The combined organic extracts were dried over sodium sulfate, filtered and concentrated. Purification of the crude material by column chromatography, eluting with 4% MeOH/dichloromethane with 0.1% NH4OH, provided (S)-2-amino-N-(4-methoxybenzyl)-3-methylbutanamide (0.770 g, 73%). LCMS (APCI+) m/z 237 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=N[N:5]([CH2:8][C:9](O)=O)[C:6]=1[CH3:7].N1C=CC=CC=1.[Cl:19][C:20]1[CH:21]=[C:22]([NH:32][C:33](=[O:44])[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)[C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:24][CH:25]=1.CN(C)[CH:47]=[O:48]>>[Cl:19][C:20]1[CH:21]=[C:22]([NH:32][C:33](=[O:44])[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:42])([F:43])[F:41])[CH:35]=2)[C:23]([N:26]2[CH2:31][CH2:30][N:29]([C:47](=[O:48])[CH2:9][CH:8]3[C:3]([CH3:12])=[C:2]([Cl:1])[C:6]([CH3:7])=[N:5]3)[CH2:28][CH2:27]2)=[N:24][CH:25]=1
Reactant: Cc1nn(CC(=O)O)c(C)c1Cl
Reactant: CN(C)C=O
Reactant: O=C(Nc1cc(Cl)cnc1N1CCNCC1)c1cccc(C(F)(F)F)c1
Solvent: c1ccncc1
Product: CC1=NC(CC(=O)N2CCN(c3ncc(Cl)cc3NC(=O)c3cccc(C(F)(F)F)c3)CC2)C(C)=C1Cl
Reaction time: 1 h
Yield: 21 %

Procedure:
To solution of (4-chloro-3,5-dimethyl-pyrazol-1-yl)-acetic acid (0.051 g, 0.160 mmol) in N,N-dimethylformamide (2 mL) is added pyridine (0.006 mL, 0.07 mmol) followed by 0.123 g (0.324 mmol) of tetramethyluroniumhydroxybenzotriazolehexaflourophosphate. The mixture stirred for 1 h. To this is added of N-(5-chloro-2-piperazin-1-yl-pyridin-3-yl)-3-trifluoromethyl-benzamide (0.031 g, 0.162 mmol). The mixture is allowed to stir overnight. The mixture is concentrated under reduced pressure and is purified by reverse phase HPLC to provide 0.010 g of N-(5-chloro-2-{4-[2-(4-chloro-3,5-dimethyl-2H-pyrrol-2-yl)-acetyl]-piperazin-1-yl}-pyridin-3-yl)-3-trifluoromethyl-benzamide in 21% yield. MS; MH+=558.8
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])#[N:2].[N:11](Cl)=[O:12].C(Cl)Cl>C(Cl)(Cl)Cl>[C:1]([C:3](=[N:11][OH:12])[C:4]([NH:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])#[N:2]
Reactant: O=NCl
Reactant: CC(C)(C)NC(=O)CC#N
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)NC(=O)C(C#N)=NO

Procedure:
The compound of the formula 5 can be prepared also by the following novel method: 2-Cyano-N-(1,1-dimethylethyl)acetamide 11 (Bhawal, B. M.; Khanapure, S. P.; Biehl, E. R.; Syn. Commun., 1990, 20, 3235) is allowed to react with nitrosyl chloride in an inert organic solvent such as CH2Cl2 or CHCl3 at moderate temperature (e.g., ambient temperature to −25° C., preferably about 0° C.). The resulting 2-cyano-N-(1,1-dimethylethyl)-2-(hydroxyimino)acetamide 13 is isolated and reduced, for example with sodium dithionite in an aqueous organic solvent, but preferably with aluminum amalgam in water at moderate temperature (e.g., ambient temperature to about 0° C., preferably about 0° C.).
Reaction SMILES: [CH2:1]([C:3]1([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[CH2:9][NH:8][C:7](=[O:10])[CH2:6][CH2:5][CH2:4]1)[CH3:2].[H-].[Na+].[CH3:21]I>C1C=CC=CC=1>[CH2:1]([C:3]1([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[CH2:9][N:8]([CH3:21])[C:7](=[O:10])[CH2:6][CH2:5][CH2:4]1)[CH3:2]
Reactant: CI
Reactant: CCC1(c2cccc(OC)c2)CCCC(=O)NC1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCC1(c2cccc(OC)c2)CCCC(=O)N(C)C1
Temperature: 40 °C

Procedure:
6-Ethyl-6-(m-methoxyphenyl)hexahydro-2H-azepin-2-one (19.6 g) in dry benzene (200 ml.) was added dropwise to a stirred refluxing suspension of sodium hydride (60% suspension in oil; 4.0 g.) in dry benzene (200 ml.) under nitrogen. After the addition had been completed the reaction mixture was heated under reflux for 4 hours and then cooled to 40° C. Methyl iodide (20 ml.) was then added and the mixture stirred and heated at 40°-55° C. overnight. After cooling, the reaction mixture was washed with water, dried over magnesium sulphate and evaporated to an orange oil which was crystallised. The product was recrystallised from light petroleum (b.p. 80°-100° C.) to give 6-ethyl-6-(m-methoxyphenyl)-1-methylhexahydro-2H-azepin-2-one (19.1 g) as colourless crystals, m.p. 69°-71° C. (Found: C, 73.2; H, 8.9; N, 5.4%. C16H23NO2 requires: C, 73.5; H, 8.9; N, 5.4 %)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH:19]3[CH2:23][CH:22]([CH2:24][S:25][C:26]4[N:30]=[CH:29][NH:28][N:27]=4)[O:21][C:20]3=[O:31])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[OH2:32].[OH-].[Li+]>O.C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([S:15]([NH:18][CH:19]([CH2:23][CH:22]([OH:32])[CH2:24][S:25][C:26]3[N:30]=[CH:29][NH:28][N:27]=3)[C:20]([OH:21])=[O:31])(=[O:16])=[O:17])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: O
Reactant: COc1ccc(-c2ccc(S(=O)(=O)NC3CC(CSc4nc[nH]n4)OC3=O)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)CSc3nc[nH]n3)C(=O)O)cc2)cc1
Reaction time: 4 h

Procedure:
To a solution of 3-[(4′-methoxy[1,1′-biphenyl]-4-yl)sulfonyl]amino-2-oxo-5-[(1H-1,2,4-triazol-3-ylthio)methyl]-tetrahydrofuran 20a (0.34 g, 0.68 mmol) in water (5 mL) and THF (5 mL) is added slowly lithium hydroxide monohydrate (290 mg, 4.2 mmol). The reaction mixture is stirred for 4 h, then concentrated to dryness. Diluted with water, the mixture is extracted twice with Et2O. The Et2O layer is discarded and the aqueous layer is neutralized carefully with 1N HCl to pH 6, then extracted three times with EtOAc. The combined EtOAc layer is washed with brine, dried over MgSO4 and concentrated to a solid which is recrystallized from EtOAc/hexane (1:4) to give the desired product as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH:20]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[C:19](=O)[C:18]3[C:17]([C:32]([O:34]CC)=O)=[CH:16][CH:15]=[CH:14][C:13]=3[NH:12]2)=[CH:7][CH:6]=1)[CH3:3].O.[NH2:38][NH2:39]>CO>[CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[NH:12][C:13]3[C:18]4[C:19](=[N:38][NH:39][C:32](=[O:34])[C:17]=4[CH:16]=[CH:15][CH:14]=3)[CH:20]2[C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:26]=2)=[CH:7][CH:6]=1)[CH3:3]
Reactant: NN
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1ccc(C(F)(F)F)cc1)C(c1ccc(CN(C)C)cc1)N2
Solvent: O
Solvent: CO
Product: CN(C)Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(C(F)(F)F)cc2)cc1
Temperature: 30 °C
Reaction time: 8 h
Yield: 34.5 %

Procedure:
A mixture of ethyl 2-(4-((dimethylamino)methyl)phenyl)-4-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-5-carboxylate (150 mg, 0.30 mmol) and hydrazine monohydrate (0.5 mL) in methanol (10 mL) was stirred at 30° C. overnight. The mixture was concentrated under reduced pressure to give crude product, which was purified by flash chromatography to give the title compound (60 mg, yield 34.5%) as a white solid. LC-MS (ESI) m/z: 465 (M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ (pp): 2.64 (s, 3H), 2.65 (s, 3H), 4.19-4.20 (d, J=4.0 Hz, 2H), 4.53-4.55 (d, J=9.2 Hz, 1H), 4.88-4.90 (d, J=9.2 Hz, 1H), 7.20-7.22 (d, J=7.6 Hz, 1H), 7.35-7.46 (m, 7H), 7.50 (s, 1H), 7.56-7.63 (m, 3H), 9.69-9.71 (br s, 1 H), 12.20 (s, 1H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:14]C(=O)OC(C)(C)C)[CH2:10][CH2:11][O:12][CH3:13])=[CH:5][CH:4]=1>C(Cl)Cl.CO>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([NH2:14])[CH2:10][CH2:11][O:12][CH3:13])=[CH:7][CH:8]=1
Reactant: COCCC(NC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COCCC(N)c1ccc(Cl)cc1
Temperature: 22 °C
Reaction time: 5 h
Yield: 87.2 %

Procedure:
Hydrogen chloride (4M in 1,4-dioxane, 0.667 mL, 2.67 mmol) was added to tert-butyl 1-(4-chlorophenyl)-3-methoxypropylcarbamate (Intermediate 99) (80 mg, 0.27 mmol) in a mixture of DCM (5 mL) and methanol (2 mL) at 22° C. The resulting solution was stirred at 22° C. for 5 hours. The mixture was concentrated and the residue was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 2M NH3/MeOH and pure fractions were evaporated to dryness to afford 1-(4-chlorophenyl)-3-methoxypropan-1-amine (47.0 mg, 88%) as a colourless oil.
Reaction SMILES: O[CH2:2][C:3]([CH2:8]O)([CH3:7])[C:4]([OH:6])=[O:5].[N:10]([CH2:13][CH2:14][O:15][C:16](=[O:20])[C:17]([CH3:19])=[CH2:18])=[C:11]=[O:12]>>[C:16]([O:15][CH2:14][CH2:13][NH:10][C:11]([CH2:8][C:3]([CH2:2][C:11](=[O:12])[NH:10][CH2:13][CH2:14][O:15][C:16](=[O:20])[C:17]([CH3:19])=[CH2:18])([CH3:7])[C:4]([OH:6])=[O:5])=[O:12])(=[O:20])[C:17]([CH3:19])=[CH2:18]
Reactant: C=C(C)C(=O)OCCN=C=O
Reactant: CC(CO)(CO)C(=O)O
Product: C=C(C)C(=O)OCCNC(=O)CC(C)(CC(=O)NCCOC(=O)C(=C)C)C(=O)O

Procedure:
2,2-di(N-methacryloxyethyl carbamoylmethyl) propionic acid (PDMA) is synthesized by reacting 2,2-Bis(hydroxymethyl)propionic acid (BHMPA) and two equivalents of Isocyanatoethylmethacrylate (IEM) as follows:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:10]2)=[CH:5][CH:4]=1.[CH:18]1[CH:23]=[CH:22][C:21]([CH2:24][Br:25])=[CH:20][CH:19]=1>CC#N>[Br-:25].[CH2:24]([CH:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[CH2:7][CH2:8][C:9]1=[N+:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[C:21]1[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=1
Reactant: COc1ccc2c(c1)C=C(N1CCCC1)CC2
Reactant: BrCc1ccccc1
Solvent: CC#N
Product: COc1ccc2c(c1)C(Cc1ccccc1)C(=[N+]1CCCC1)CC2
Product: [Br-]
Reaction time: 1 h

Procedure:
To a mixture of 1-(7-methoxy-3,4-dihydro-naphthalen-2-yl)-pyrrolidine (320 g, 1.4 mol) in MeCN (1000 mL) was added BnBr (263 g, 1.54 mol) dropwise at room temperature and stirred for 1 h. Then the solvent was evaporated in vacuo to give crude 1-(1-benzyl-7-methoxy-3,4-dihydro-1H-naphthalen-2-ylidene)-pyrrolidinium bromide which was directly used for next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:34])[C@@H:9]([CH3:33])[C:10]([NH:12][C@@H:13]([CH:30]([CH3:32])[CH3:31])[C:14]([N:16]1[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH2:18][C@H:17]1[C:25]([O:27]CC)=[O:26])=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>C1COCC1.CO.O>[C:1]([O:5][C:6]([N:8]([CH3:34])[C@@H:9]([CH3:33])[C:10]([NH:12][C@@H:13]([CH:30]([CH3:31])[CH3:32])[C:14]([N:16]1[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH2:18][C@H:17]1[C:25]([OH:27])=[O:26])=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@@H]1Cc2cccnc2N1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1c2ncccc2C[C@H]1C(=O)O
Reaction time: 1 h
Yield: 100.6 %

Procedure:
A solution of (S)-ethyl 1-((S)-2-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-3-methylbutanoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (1.9 g, 3.99 mmol, Eq: 1.00) in THF (36 mL) and MeOH (12 mL) was cooled in an ice bath. To this solution was added a solution of lithium hydroxide monohydrate (0.5 g, 11.9 mmol, Eq: 2.99) in water (12 mL) and the cooling bath was removed. After 1 h, the reaction was quenched by adding 0.1 M aqueous KHSO4 (200 mL) and the mixture was extracted with DCM (2×100 mL). The combined DCM layers were dried over Na2SO4 and concentrated in vacuo. The residue was azeotroped with n-heptane (1×100 mL) to give (S)-1-((S)-2-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-3-methylbutanoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (1.8 g) as a white solid, m/z=449 (M+H).