Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[O:16])=[CH:13][N:12]=[C:11]([NH:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[N:10]=1.[CH2:32]([N:35]=[C:36]=[O:37])[CH2:33][CH3:34]>>[CH2:32]([NH:35][C:36]([N:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:11]2[N:10]=[C:9]([NH2:8])[C:14]([C:15](=[O:16])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])=[CH:13][N:12]=2)[CH2:27][CH2:28]1)=[O:37])[CH2:33][CH3:34]
Reactant: CCCN=C=O
Reactant: COc1ccccc1C(=O)c1cnc(NC2CCNCC2)nc1N
Solvent: O=C(O)C(F)(F)F
Product: CCCNC(=O)N1CCC(Nc2ncc(C(=O)c3ccccc3OC)c(N)n2)CC1

Procedure:
The same procedure as described in Example 25 was used, starting from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(2-methoxy-phenyl)-methanone trifluoroacetic acid salt, Example 11, and propyl isocyanate (Aldrich), to give 4-[4-Amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid propylamide. HRMS, observed:413.2299; Calcd for (M+H)+: 413,2296.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15]Cl)[CH:10]=2)=[N:6][CH:7]=1.[P:17]([O:24]CC)([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20].C(OCC)(=O)C>CCCCCCC>[Br:1][C:2]1[CH:3]=[N:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=2)[CH2:15][P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])=[N:6][CH:7]=1
Reactant: ClCc1cccc(Oc2ncc(Br)cn2)c1
Reactant: CCOP(OCC)OCC
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCOP(=O)(Cc1cccc(Oc2ncc(Br)cn2)c1)OCC
Temperature: 150 °C
Reaction time: 16 h
Yield: 83.5 %

Procedure:
5-Bromo-2-(3-(chloromethyl)phenoxy)pyrimidine (810 mg, 2.70 mmol) was treated with triethyl phosphite (1 mL, 2.2 mmol), and heated to 150° C. After 16 h, the reaction mixture was removed from the heat and ethyl acetate (about 3 mL) followed by heptane were added. As the reaction mixture cooled an oily precipitate formed. The mixture was made homogenous by addition of ethyl acetate. Heptane was added dropwise until a white solid precipitated. Additional heptane was added and the solid was filtered, washed with heptane and dried in vacuo to afford the title compound (0.737 g, 68% yield) as a white solid. MS (APCI) M+1=401; 1H NMR (400 MHz, CDCl3) δ ppm 1.26 (t, J=6.92 Hz, 6H) 3.18 (d, J=21.64 Hz, 2H) 3.98-4.10 (m, 4H) 7.06-7.11 (m, 1H) 7.15 (q, J=2.01 Hz, 1H) 7.20-7.26 (m, 1H) 7.35-7.42 (m, 1H) 8.56 (s, 2H).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)=[CH:6][CH:7]=1.[CH:13]([NH:15][NH2:16])=O>C(O)CCC>[S:10]1[CH:11]=[CH:12][C:8]([C:5]2[CH:6]=[CH:7][C:2]3[N:3]([CH:13]=[N:15][N:16]=3)[N:4]=2)=[CH:9]1
Reactant: NNC=O
Reactant: Clc1ccc(-c2ccsc2)nn1
Solvent: CCCCO
Product: c1cc(-c2ccc3nncn3n2)cs1

Procedure:
A mixture of 1.5 g. of 3-chloro-6-(3-thienyl)pyridazine and 0.96 g. of formic acid hydrazide in 50 ml. of n-butyl alcohol is heated at the reflux temperature for 48 hours. The reaction mixture is concentrated free of volatiles and the residue is partitioned between dilute sodium hydroxide and methylene chloride. The organic layer is dried over anhydrous sodium sulfate, filtered and evaporated. The residue is recrystallized from methylene chloride-hexane to give a solid. The solid is recrystallized from acetone-hexane to provide 1.0 g. of the product of the Example as a orange-cream solid, m.p. 189°-192° C.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[H-].[Na+].[CH3:10][O:11][CH2:12][CH2:13][O:14][CH2:15]Cl.O>CN(C)C=O>[CH3:10][O:11][CH2:12][CH2:13][O:14][CH2:15][O:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:7]
Reactant: OCCCCCO
Reactant: COCCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOCOCCCCCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.4 %

Procedure:
A solution of 50.00 g of 1,5-pentanediol dissolved in 100 ml of dimethylformamide was added dropwise to a mixture of 23.00 g of sodium hydride (as a 55% w/w dispersion in mineral oil) in 300 ml of dimethylformamide, whilst ice-cooling at 5° to 7° C. The mixture was stirred at room temperature for 1 hour, after which 65.79 g of 2-methoxyethoxymethyl chloride dissolved in 100 ml of dimethylformamide were added dropwise, whilst ice-cooling at 5° to 7° C. The mixture was stirred at room temperature for 3 hours, after which it was poured into 2.5 liters of water and then extracted five times with methylene chloride. The combined extracts were washed with water, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was subjected to column chromatography through 850 g of silica gel, and 48.40 g of the title compound were obtained, as a colorless oil, from those fractions eluted with mixtures of methylene chloride and methanol ranging from 98:2 to 95:5 by volume.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([O:10]C)=[CH:6][C:4]=1[NH2:5].C[O:13][C:14]1[CH:22]=[CH:21][C:17](C(Cl)=O)=[CH:16][CH:15]=1>>[OH:13][C:14]1[CH:22]=[CH:21][C:17]([C:1]2[O:2][C:3]3[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:4]=3[N:5]=2)=[CH:16][CH:15]=1
Reactant: COc1ccc(OC)c(N)c1
Reactant: COc1ccc(C(=O)Cl)cc1
Product: Oc1ccc(-c2nc3cc(O)ccc3o2)cc1

Procedure:
The title compound was prepared in substantially the same manner as described in Example 1, from 2,5-dimethoxyaniline, and 4-methoxybenzoyl chloride and was obtained as a light yellow solid, m.p. 264–267° C.; MS m/e 228 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([C:15]([OH:17])=O)[CH2:6][C:5]2=1.C1N=C[N:20](C(N2C=NC=C2)=O)C=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([C:15]([NH2:20])=[O:17])[CH2:6][C:5]2=1
Reactant: O=C(O)C1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: NC(=O)C1CCc2[nH]c3ccc(Cl)cc3c2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid (7c, 5.67 g, 22.71 mmole) dissolved THF (70 ml). N,N-carbonyldiimidazole (5.52 g, 44.81 mmole) was added. The reaction was stirred at ambient temperature for 3 hours. Ammonia was bubbled in for 1½ hours. The solid was filtered and discarded. Ethyl acetate (50 ml) was added to the filtrate and washed with citric acid 2 times, then the ethyl acetate phase was washed with 5% sodium bicarbonate and brine. The organic phase was concentrated in vacuo. The product was crystallized from the solution and filtered yielding a white solid, 4.39 g, 78%; mp. 247-248° C.
Reaction SMILES: [I-].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[CH:12][NH:13][CH:14]=2)=[CH:6][CH:5]=1.I[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([N:13]2[CH:14]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=3)[N:11]=[CH:12]2)=[CH:17][CH:18]=1
Reactant: COc1ccc(-c2c[nH]cn2)cc1
Reactant: COc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2cn(-c3ccc(OC)cc3)cn2)cc1
Temperature: 120 °C
Reaction time: 48 h
Yield: 56.5 %

Procedure:
10 mg cupper (I) iodide, 20 mg trans-N,N′-dimethyl-1,2-cyclohexyldiamine was added to 1.1 g 4-(4-methoxy-phenyl)-1H-imidazole, 1.5 g 1-iodo-4-methoxy-benzene and 1.95 g cesium carbonate in 5 mL DMF under argon. The reaction was stirred 48 h at 120° C. in a closed microwave bottle under argon. Water was added and the reaction was extracted with ethyl acetate. The organic layer was dried and evaporated. The residue was purified by chromatography on Alox (50 kg, Merck (Darmstadt), Bestell-Nr. 1.01097.9050 activity: II-III) (gradient: dichlormethane/EtOAC 9:1-8:2) to yield 1 g of the desired compound.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([CH:9]2[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][CH2:10]2)[CH:5]=[CH:4][C:3]=1[C:20]1(O)[CH2:25][CH2:24][CH:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH3:34])=[C:28]([F:35])[C:27]=2[F:36])[CH2:22][CH2:21]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[F:1][C:2]1[C:7]([F:8])=[C:6]([CH:9]2[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][CH2:10]2)[CH:5]=[CH:4][C:3]=1[C:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH3:34])=[C:28]([F:35])[C:27]=2[F:36])[CH2:22][CH:21]=1
Reactant: CCCCCC1CCC(c2ccc(C3(O)CCC(c4ccc(OCC)c(F)c4F)CC3)c(F)c2F)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCC1CCC(c2ccc(C3=CCC(c4ccc(OCC)c(F)c4F)CC3)c(F)c2F)CC1
Temperature: 30 °C
Yield: 50.2 %

Procedure:
The compound (51) (9.7 g), p-toluenesulfonic acid (0.15 g) and toluene (200 ml) were mixed, and the mixture was heated under reflux for 2 hours while water being distilled was removed. The reaction mixture was cooled to 30° C., and then water (200 ml) and toluene (300 ml) were added thereto and mixed. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and extraction into an organic phase was carried out. The organic phase obtained was fractionated, washed sequentially with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solution obtained was purified with a fractional operation by means of column chromatography using a mixed solvent of heptane and toluene (heptane:toluene=2:3 by volume) as the eluent and silica gel as the stationary phase powder. The solvent was distilled off, and the residue obtained was purified with a fractional operation by means of column chromatography using toluene as the eluent and silica gel as the stationary phase powder. The product was further purified by means of recrystallization from a mixed solvent of Solmix A-11 and ethyl acetate (Solmix A-11:ethyl acetate=2:1 by volume) and dried, giving 4.7 g of 1-(4-(2,3-difluoro-4-(4-pentylcyclohexyl)phenyl)cyclohex-3-enyl)-4-ethoxy-2,3-difluorobenzene (No. 12). The yield based on the compound (10) was 49.8%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]([NH2:13])([CH3:12])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([C:25](O)=[O:26])=[CH:19]2>ClCCl.CN(C)C=O>[CH3:1][O:2][C:3](=[O:14])[C:4]([NH:13][C:25]([C:20]1[NH:21][C:22]2[C:18]([CH:19]=1)=[CH:17][C:16]([Cl:15])=[CH:24][CH:23]=2)=[O:26])([CH3:12])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)C(C)(N)Cc1ccccc1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)C(C)(Cc1ccccc1)NC(=O)c1cc2cc(Cl)ccc2[nH]1

Procedure:
Racemic 2-amino-2-methyl-3-phenyl-propionic acid methyl ester (200 mg, 0.87 mmol) and 5-chloro-1H-indole-2-carboxylic acid (170 mg, 0.87 mmol) were coupled according to Procedure A (2:1 dichloromethane/dimethylformamide solvent) and the product purified by chromatography on silica gel eluted with 10% ethyl acetate in hexanes. Yield 286 mg, 89%; HPLC (60/40) 9.63 minutes (85%); TSPMS 371/373 (MH+, 100%);
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([C:18]([OH:20])=O)[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.P([N:44]=[N+:45]=[N-:46])(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O>C1COCC1>[C:1]([O:5][C:6]([C:8]1([C:18]([N:44]=[N+:45]=[N-:46])=[O:20])[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C1(C(=O)O)CCc2ccccc2C1
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C1(C(=O)N=[N+]=[N-])CCc2ccccc2C1
Yield: 58 %

Procedure:
3,4-Dihydro-1H-naphthalene-2,2-dicarboxylic acid tert-butyl ester from Example 43A was dissolved in THF (50 mL) followed by addition of Et3N (5.05 g, 50 mmol) and (PhO)2PON3 (11 g, 40 mmol) at 0° C. After 3 hours the volatiles were removed under reduced pressure and the residue purified by column chromatography to provide the titled compound (13.1 g, 58% over three steps).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[CH:5]=[CH:6][C:7]=1F.[F:12][C:13]([F:17])([F:16])[CH2:14][OH:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[CH:5]=[CH:6][C:7]=1[O:15][CH2:14][C:13]([F:17])([F:16])[F:12]
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Reactant: OCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ccc(OCC(F)(F)F)c(Br)c1
Temperature: 90 °C
Yield: 97 %

Procedure:
3-Bromo-4-fluoronitrobenzene (1.0 eq) was added to a stirring solution of 2,2,2-trifluoroethanol (1.1 eq) and potassium carbonate (2.0 eq) in DMF. The solution was heated for 18 hours at 90° C. at which time no starting material was apparent by LCMS. The solution was cooled and filtered through Celite and the plug washed with EtOAc. The organic layer is then washed with brine and water, dried over MgSO4, filtered and concentrated to yield the desired product 97% pure, 80% yield. LC Rt=2.975 min. MH+=302.0
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6](Cl)[N:5]=[C:4]([S:12][CH3:13])[N:3]=1.CN(C)[C:16](=[O:18])C.O1CCCC1.[H-].[Na+]>CO>[Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([O:18][CH3:16])[N:5]=[C:4]([S:12][CH3:13])[N:3]=1
Reactant: CSc1nc(Cl)c(C(=O)O)c(Cl)n1
Reactant: CC(=O)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1nc(SC)nc(Cl)c1C(=O)O
Reaction time: 0.33 h

Procedure:
A mixture of 4,6-dichloro-5-carboxy-2-methylthiopyrimidine (prepared in Example 320(1)) 5.00 g, N,N-dimethylacetamide 50 ml, tetrahydrofuran 20 ml and sodium hydride (60%) 1.673 g is stirred for 20 minutes on an ice bath. Methanol 5 ml is dropped thereto over a period of 30 minutes and the mixture is stirred for 15 minutes. The reaction mixture is diluted with a 10% aqueous citric solution and extracted with ethyl acetate. The organic layer is washed, dried and concentrated in vacuo. The resulting solid is triturated with hexane in ice to give 4-chloro-5-carboxy-6-methoxy-2-methylthiopyrimidine as a slightly brown crystalline powder, 4.61 g. mp 179-181° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10]O)[CH:6]=[CH:5][N:4]=1.C(Br)(Br)(Br)[Br:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[Br:13][CH2:10][CH2:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(CCO)ccn1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1cc(CCBr)ccn1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
A mixture of 2-(2-methoxypyridin-4-yl)ethanol (commercially available) (700 mg, 4.57 mmol,), CBr4 (2.27 g, 6.85 mmol) and triphenylphosphine (1.8 g, 6.85 mmol) in 75 mL toluene was stirred at RT for 64 h. The mixture was filtered over a silica-plug and washed with toluene. The filtrate concentrated under vacuum to yield the crude product. The residue was purified by column chromatography on silica eluting with a gradient formed from heptane and EtOAc to yield, after evaporation of the product containing fraction, 624 mg (63%) of the title compound as colourless liquid. MS (m/e): 216.2 (MH+).
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:17][C:18](=[O:38])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:23][CH:22]=1)[CH:12]=[CH:11]2)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:28]([O:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][CH2:19][C:18](=[O:38])[CH2:17][N:13]2[C:14]3[C:10](=[CH:9][C:8]([C:6]([OH:7])=[O:5])=[CH:16][CH:15]=3)[CH:11]=[CH:12]2)=[CH:22][CH:23]=1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCCCOc1ccc(OCC(=O)Cn2ccc3cc(C(=O)OC(C)(C)C)ccc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCOc1ccc(OCC(=O)Cn2ccc3cc(C(=O)O)ccc32)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
50 mg (0.096 mmol) tert-butyl-1-[3-(4-decyloxyphenoxy)-2-oxopropyl]indole-5-carboxylate are dissolved in 15 ml absolute dichloromethane and mixed with 0.82 g (7.19 mmol) trifluoroacetic acid. Having stirred at room temperature for 4 hours, the batch is concentrated to dryness on the rotary evaporator. Three admixtures with 10 ml of a mixture of petroleum ether and ethyl acetate (4:1) each and respective concentration to dryness on the rotary evaporator leave as a crude product a solid which is purified on an RP-HPLC column by means of chromatography (stationary phase: cromasil, flow agent: acetonitrile/water 90:10).
Reaction SMILES: N.[Na].[CH3:3][N:4]([CH2:6][C:7]#[CH:8])[CH3:5].Cl.Br[CH2:11][CH2:12][CH2:13][NH2:14]>C(OCC)C>[CH3:3][N:4]([CH3:5])[CH2:6][C:7]#[C:8][CH2:11][CH2:12][CH2:13][NH2:14]
Reactant: NCCCBr
Reactant: C#CCN(C)C
Agent: Cl
Agent: N
Agent: [Na]
Solvent: CCOCC
Product: CN(C)CC#CCCCN
Reaction time: 1 h
Yield: 16 %

Procedure:
A flask fitted with a dry ice condenser was charged with liquid ammonia (250 ml). To this was added sodium (0.24 mol) in portions together with a few grains of ferric nitrate; subsequently dimethylaminoprop-2-yne (0.24 mol) was added. The reaction mixture was stirred for one hour, 3-bromopropylamine hydrochloride (0.24 mol) was added in portions and the mixture stirred for a further two hours. Anhydrous diethyl ether (150 ml) was added and excess ammonia was allowed to evaporate overnight. The reaction mixture was dissolved in methanol and evaporated under reduced pressure to afford a residue, which was partitioned between chloroform and water. The aqueous layer was washed with chloroform (5×150 ml). The chloroform extracts were combined, dried over MgSO4, filtered and evaporated under reduced pressure to give 6-dimethylaminohex-4-ynylamine as an oil (5.4 g).
Reaction SMILES: [F:1][CH:2]([F:25])[O:3][CH2:4][C@@H:5]([NH:17][C:18](=O)[O:19]C(C)(C)C)[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)=[O:7].F[C:27](F)(F)C(O)=O>ClCCl>[C:18]([NH:17][C@H:5]([CH2:4][O:3][CH:2]([F:25])[F:1])[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)=[O:7])(=[O:19])[CH3:27]
Reactant: CC(C)(C)OC(=O)N[C@H](COC(F)F)C(=O)NCc1ccc(F)cc1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N[C@H](COC(F)F)C(=O)NCc1ccc(F)cc1
Yield: 65.7 %

Procedure:
tert-Butyl {(1R)-1-[(difluoromethoxy)methyl]-2-[(4-fluorobenzyl)amino]-2-oxoethyl}carbamate (400 mg, 1.1 mmol) was stirred with trifluoroacetic acid (1.5 mL) and dichloromethane (2.5 mL) in an ice bath for an hour. The reaction mixture was concentrated, mixed with acetic anhydride-pyridine (1:1.6 mL) at room temperature for 30 minutes and then diluted with ethyl acetate, washed with saturated sodium bicarbonate, brine, 0.5N HCl and brine again. The organic layer was dried, concentrated, and triturated with diethyl ether to give (2R)-2-(acetylamino)-3-(difluoromethoxy)-N-(4-fluorobenzyl)propanamide (220 mg, 65.7%) as a white solid. Mp: 162.7° C. 1H NMR (300 MHz, CDCl3): δ(ppm) 7.24 (dd, 2H), 7.03 (t, 2H), 6.78 (w, 1H), 6.35 (d, 1H), 6.24 (wt, 1H), 4.71 (m, 1H), 4.44 (d, 2H), 4.24 (dd, 1H), 4.01 (dd, 1H) and 2.05 (s, 3H).
Reaction SMILES: [C:1](=[O:4])([O-])N.[CH3:5][O:6][C:7](=[O:20])[NH:8][C:9]1[S:10][C:11]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:12]=2[N:13]=1>>[CH3:5][O:6][C:7](=[O:20])[NH:8][C:9]1[S:10][C:11]2[C:17]([N:13]3[CH2:9][CH2:1][O:4][CH2:11][CH2:12]3)=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:12]=2[N:13]=1
Reactant: COC(=O)Nc1nc2c(OC)cccc2s1
Reactant: NC(=O)[O-]
Product: COC(=O)Nc1nc2c(OC)ccc(N3CCOCC3)c2s1
Yield: 58 %

Procedure:
Carbamate formation using the same procedure as for (4-methoxy-benzothiazol-2-yl)-carbamic acid methyl ester yields the product as off-white solid in 58% yield. MS: m/e=324 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([OH:11])[N:8]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:7]=1)=[O:5])[CH3:2].[CH2:18](O)[C:19]([CH3:22])([CH3:21])[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([O:11][CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[N:8]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)Cn1nc(C(=O)OCC)cc1O
Reactant: CC(C)(C)CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)Cn1nc(C(=O)OCC)cc1OCC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
To an ice cold mixture of 50 mg (0.21 mmol) of 1-Ethoxycarbonylmethyl-5-hydroxy-1H-pyrazole-3-carboxylic acid ethyl ester in 2 mL of tetrahydrofuran was added 49 mg (0.25 mmol) of neopentyl alcohol, 108 mg (0.41 mmol) of triphenylphosphine, followed by 0.081 mL (0.41 mmol) of diisopropyl azodicarboxylate (DIAD) and the mixture was allowed to warm up to rt and stirred at rt overnight. The reaction mixture was then concentrated and the residue was chromatographed on silica gel (3:1 hexane:ethyl acetate) to give 46 mg (70%) of 5-(2,2-dimethyl-propoxy)-1-ethoxycarbonylmethyl-1H-pyrazole-3-carboxylic acid ethyl ester LC-MS calcd. for C15H24N2O5 [M++H]: 313.2; found: 313.2.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13]([C:15]#[N:16])[CH:12]=[CH:11][C:10]=1[OH:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:18].[CH2:19]([O:21]CC)C>CO>[ClH:18].[C:1]([C:9]1[CH:14]=[C:13]([CH:15]=[N:16][O:21][CH3:19])[CH:12]=[CH:11][C:10]=1[OH:17])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(O)c(C(=O)c2ccccc2)c1
Reactant: CCOCC
Agent: Cl
Solvent: CO
Product: CON=Cc1ccc(O)c(C(=O)c2ccccc2)c1

Procedure:
A suspension of 214 g of 2-benzoyl-4-cyanophenol in 1.7 liters of anhydrous methanol was saturated with anhydrous hydrogen chloride, while being cooled in ice and stirred. After having been stirred overnight at room temperature, the mixture was mixed with a large volume of ethyl ether. The precipitated crystals were collected by filtration and dried to yield 156 g of 2-benzoyl-4-methoxyiminomethylphenol hydrochloride.
Reaction SMILES: [NH:1]([C:3](=[O:23])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:18][CH2:17][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)=[O:5])[NH2:2].[F:24][C:25]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:26]=1[N:33]=[C:34]=S>>[F:24][C:25]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:26]=1[NH:33][C:34]1[O:23][C:3]([C:4]([NH:6][C:7]2[CH:8]=[CH:9][C:10]([C@H:13]3[CH2:14][CH2:15][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:17][CH2:18]3)=[CH:11][CH:12]=2)=[O:5])=[N:1][N:2]=1
Reactant: Fc1cc(F)c(N=C=S)cc1F
Reactant: COC(=O)[C@H]1CC[C@H](c2ccc(NC(=O)C(=O)NN)cc2)CC1
Product: COC(=O)[C@H]1CC[C@H](c2ccc(NC(=O)c3nnc(Nc4cc(F)c(F)cc4F)o3)cc2)CC1

Procedure:
Following the procedure of Example 105 except that methyl trans-4-(4-{[hydrazino(oxo) acetyl]amino}phenyl)cyclohexanecarboxylate (Intermediate 44) and 2,4,5-trifluorophenylisothiocyanate were used as starting materials the title compound was obtained as solid; 1H NMR δ 1.47 (1H, s), 1.49 (2H, d), 1.52 (1H, s), 1.85 (2H, d), 2.01 (2H, d), 2.45 (1H+DMSO, m), 2.53-2.56 (1H, m), 3.62 (3H, s), 7.22-7.24 (2H, m), 7.68 (1H, s), 7.71 (2H, q), 8.15-8.18 (1H, m), 10.96 (1H, s), 11.04 (1H, s) MS m/e MH+ 475.