Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[CH3:5][O:6][C:7]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:10]2[NH:11][C:12](=[O:16])[CH2:13][NH:14][CH2:15][C:9]=2[CH:8]=1.[C:22](O)(=O)[CH3:23].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(C(F)(F)F)=O.O.C(O)C>[CH3:5][O:6][C:7]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:10]2[NH:11][C:12](=[O:16])[CH2:13][N:14]([CH2:22][CH2:23][O:4][CH3:1])[CH2:15][C:9]=2[CH:8]=1
Reactant: CC(=O)O
Reactant: COc1cc2c(cc1[N+](=O)[O-])NC(=O)CNC2
Reactant: O=C([O-])[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COCCN1CC(=O)Nc2cc([N+](=O)[O-])c(OC)cc2C1
Yield: 38 %

Procedure:
A solution of 1,1,2-(trimethoxy)ethane (2.0 g, 16.4 mmol) in TFA/H2O (5 mL, 1/1 vol.) was stirred for five minutes at 50° C. The mixture was cooled to room temperature and neutralized to pH 6-7 by the addition of microporous carbonate (MP-CO3) with stirring. This was filtered into a solution of 7-methoxy-8-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (375 mg, 1.58 mmol) in ethanol (40 mL). The MP-CO3 was washed further with ethanol (10 mL) into the reaction mixture. To this was added acetic acid (0.36 mL, 6.34 mmol) and the mixture was stirred for two hours at room temperature before being treated with sodium triacetoxyborohydride (2.0 g, 9.4 mmol) and stirred at room temperature for an additional 18 hours. The mixture was concentrated, dissolved in dichloromethane, washed with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered and concentrated. Flash chromatography over silica gel (0-10% MeOH-EtOAc) gave 7-methoxy-4-(2-methoxy-ethyl)-8-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (175 mg, 38%); 1H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 7.61 (s, 1H), 7.32 (s, 1H), 3.91 (s, 6H), 3.44 (t, J=6 Hz, 2H), 3.41 (s, 2H), 2.69 (t, J=6 Hz, 2H); MS (m/e) 296 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:5]=1[O:6][CH2:7][CH2:8][OH:9])([O-])=O.O.[H][H]>[Pt].C(O)(C)C>[NH2:1][C:4]1[CH:13]=[C:12]([NH2:14])[CH:11]=[CH:10][C:5]=1[O:6][CH2:7][CH2:8][OH:9]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(OCCO)c([N+](=O)[O-])c1
Agent: [Pt]
Solvent: CC(C)O
Solvent: O
Product: Nc1ccc(OCCO)c(N)c1
Temperature: 20 °C
Yield: 127.9 %

Procedure:
A 1 l autoclave reactor was filled with 120 g of 2-(2′,4′-dinitrophenoxy)ethanol, 3 g of a 1% platinum/carbon catalyst which included 50% water, and 400 ml of isopropanol. At a hydrogen pressure of 1 MPa and a temperature of 100° C., hydrogenation was carried out for 10 h. The system was then cooled to 20° C., and the reaction mixture was added dropwise under a nitrogen atmosphere through a filter into an initial charge of 240 g of 37% strength hydrochloric acid which had been previously flushed repeatedly with nitrogen. The resulting suspension was heated at reflux temperature for about 30 min and then cooled to 10° C. The product obtained after filtration was washed once with isopropanol to give 113.1 g of 2-(2′,4′-diamino-phenoxy)ethanol (89.1% yield) in 98% purity. Measuring the degrees of transmission of a 0.1% strength solution of the product in water in accordance with DIN 55945 gave, as results, Tx=99.4, Ty=98.9 and Tz=98.2.
Reaction SMILES: CS(N)(=O)=O.[N:6]1([S:10]([NH2:13])(=[O:12])=[O:11])[CH2:9][CH2:8][CH2:7]1.C(C1(COC2C(C3CC3)=CC(C(O)=O)=C(F)C=2)C2CC3CC(CC1C3)C2)#N.[Cl:41][C:42]1[C:43]([O:52][CH:53]2[CH2:58][CH2:57][C:56]([F:60])([F:59])[CH2:55][CH2:54]2)=[CH:44][C:45]([F:51])=[C:46]([CH:50]=1)[C:47](O)=[O:48]>>[N:6]1([S:10]([NH:13][C:47](=[O:48])[C:46]2[CH:50]=[C:42]([Cl:41])[C:43]([O:52][CH:53]3[CH2:58][CH2:57][C:56]([F:60])([F:59])[CH2:55][CH2:54]3)=[CH:44][C:45]=2[F:51])(=[O:12])=[O:11])[CH2:9][CH2:8][CH2:7]1
Reactant: NS(=O)(=O)N1CCC1
Reactant: O=C(O)c1cc(Cl)c(OC2CCC(F)(F)CC2)cc1F
Agent: CS(N)(=O)=O
Agent: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)C2CC3CC(C2)CC1C3
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(Cl)c(OC2CCC(F)(F)CC2)cc1F

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace methanesulfonamide with azetidine-1-sulfonamide and to replace 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 5-chloro-4-((4,4-difluorocyclohexyl)oxy)-2-fluorobenzoic acid, the title compound was obtained as a colorless solid (0.028 g, 19%): 1H NMR (300 MHz, DMSO-d6) δ 11.80 (br s, 1H), 7.78 (d, J=7.5 Hz, 1H), 7.38 (d, J=12.4 Hz, 1H), 4.85 (br s, 1H), 4.00 (t, J=7.7, 7.7 Hz, 4H), 2.18-1.86 (m, 10H); 19F NMR (282 MHz, DMSO-d6) δ −92.2 (d, J=231 Hz, 1F), −98.5 (d, J=231 Hz, 1F), −110.1 (s, 1F); MS (ES−) m/z 425.1, 427.1 (M−1).
Reaction SMILES: [C-:1]#[N:2].[Na+].[Cl-].[NH4+:5].[CH:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CO>[NH2:5][CH:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:1]#[N:2]
Reactant: O=Cc1ccccc1
Reactant: [C-]#N
Reactant: [NH4+]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: N#CC(N)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 35.6 %

Procedure:
To a 0.3 ml aqueous solution of 46 mg of sodium cyanide and 55 mg of ammonium chloride was added a solution of 100 mg of benzaldehyde in 0.3 ml of methanol, and the resulting mixture was stirred at room temperature for 5 hours. After adding aqueous solution of ammonium chloride to the reaction mixture, it was extracted with ethyl acetate twice. The organic layer was washed successively with a saturated aqueous solution of ammonium chloride and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. Then, the crude product was purified and separated by LC-MS, to give 44.2 mg of the title compound as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]2)=[CH:4][CH:3]=1.Br[C:20]1[C:21](=[O:28])[N:22]([CH3:27])[CH:23]=[C:24]([Br:26])[N:25]=1.C(N(CC)CC)C>C(O)(C)C>[Br:26][C:24]1[N:25]=[C:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH:8]3[CH2:9][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:11]3)=[CH:6][CH:7]=2)[C:21](=[O:28])[N:22]([CH3:27])[CH:23]=1
Reactant: Cn1cc(Br)nc(Br)c1=O
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc(N)cc2)C1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Cn1cc(Br)nc(Nc2ccc(C3CN(C(=O)OC(C)(C)C)C3)cc2)c1=O
Yield: 78.5 %

Procedure:
A mixture of 298a (500 mg, 2.02 mmol), 3,5-dibromo-1-methylpyrazin-2(1H)-one (536 mg, 2.02 mmol) and triethylamine (0.6 mL, 4.04 mmol) in isopropanol (10 mL) was heated at reflux for 4 days. The solvent was evaporated in vacuo and the residue was purified on reverse phase Combi-flash to afford 298b (690 mg, 66%). MS: [M+H]+ 435.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].C(Cl)(=O)C([Cl:15])=O.CN(C=O)C>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([Cl:15])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccc(Br)c1F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cccc(Br)c1F
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 98.5 %

Procedure:
A suspension of 3-bromo-2-fluorobenzoic acid (1.009 g, 4.61 mmol) in DCM (25 mL) was stirred at rt and treated with oxalyl chloride (2.016 mL, 23.04 mmol), followed by a drop of DMF, causing gas evolution to commence. After 2.5 h, the solution was heated to boiling for 1-2 min and allowed to cool to rt. After 3 h total, the solution was concentrated to provide 3-bromo-2-fluorobenzoyl chloride as a dark yellow liquid (1.078 g, 99%). A portion of this (200 mg, 0.842 mmol) was dissolved in THF (1.5 mL) and added to a solution of dimethylamine (2 M in methanol, 2.0 mL, 4.00 mmol) in THF (2 mL). The mixture was stirred at rt for 18 h, then was concentrated. The residue was dissolved in EtOAc, washed sequentially with 1 M hydrochloric acid, NaHCO3 (aq) and brine, and dried and concentrated to provide 3-bromo-2-fluoro-N,N-dimethylbenzamide as a light yellow oil (192 mg, 93%). 1H NMR (400 MHz, chloroform-d) δ 7.60 (ddd, J=8.1, 6.5, 1.6 Hz, 1H) 7.32 (ddd, J=7.6, 5.9, 1.6 Hz, 1H) 7.09 (td, J=7.8, 0.7 Hz, 1H) 3.14 (s, 3H) 2.93 (d, J=1.5 Hz, 3H). Mass spectrum m/z 246, 248 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:22][O:21][C:20]3[CH:23]=[C:24]4[C:28](=[CH:29][C:19]1=3)[CH2:27][CH2:26][O:25]4)[C:5](=[O:18])[N:6]2[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.BrC1C=CC=C2C=1C1(C3=CC4OCOC=4C=C3OC1)C(=O)[N:35]2[CH2:40][CH2:41][CH2:42][CH2:43][CH3:44].N1C=CC=C(B(O)O)C=1.CN(C)C1N=CC(B(O)O)=CC=1>>[N:35]1[CH:40]=[CH:41][CH:42]=[C:43]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[C:4]2([CH2:22][O:21][C:20]4[CH:23]=[C:24]5[C:28](=[CH:29][C:19]2=4)[CH2:27][CH2:26][O:25]5)[C:5](=[O:18])[N:6]3[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:44]=1
Reactant: CCCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Br)cccc21
Reactant: O=C1N(Cc2ccccn2)c2cccc(Br)c2C12COc1cc3c(cc12)CCO3
Agent: CN(C)c1ccc(B(O)O)cn1
Agent: OB(O)c1cccnc1
Product: O=C1N(Cc2ccccn2)c2cccc(-c3cccnc3)c2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 4, and making non-critical variations using 4′-bromo-1′-(pyridin-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 4′-bromo-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and pyridin-3-ylboronic acid to replace [6-(dimethylamino)pyridin-3-yl]boronic acid, the title compound was obtained (9%) as a colorless solid: mp>200° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.52 (d, 1H), 8.42 (d, 1H), 7.96 (s, 1H), 7.79 (t, 1H), 7.40 (d, 1H), 7.29 (t, 2H), 7.18-7.08 (m, 2H), 7.00 (d, 1H), 6.81 (d, 1H), 6.72 (s, 1H), 5.98 (s, 1H), 5.08 (ABq, 2H), 4.56-4.40 (m, 4H), 3.10-2.90 (m, 2H); MS (ES+) m/z 448.5 (M+1).
Reaction SMILES: [Cl:1][C:2]([F:8])(I)[C:3]([F:6])([F:5])[Cl:4].[CH2:9]([Si](C)(C)C)[CH:10]=[CH2:11]>>[Cl:1][C:2]([F:8])([C:3]([Cl:4])([F:6])[F:5])[CH2:11][CH:10]=[CH2:9]
Reactant: C=CC[Si](C)(C)C
Reactant: FC(F)(Cl)C(F)(Cl)I
Product: C=CCC(F)(Cl)C(F)(F)Cl

Procedure:
A mixture of 279 mg (1.0 mmol) of 1,2-dichloro-1-iodotrifluoroethane and 114 mg (1.0 mmol) of allyltrimethylsilane was sealed in a Pyrex glass tube and externally radiated with a high pressure mercury lamp (400 W) in an ice-bath for 3 hours to obtain 4,5-dichloro-4,5,5-trifluoro-1-pentene (Compound 39) in a yield of 60%.
Reaction SMILES: [F:1][C:2]1[C:10]2[N:11]([C:15]3[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=3[F:22])[C:12](=[O:14])[NH:13][C:9]=2[C:8]2[O:7][CH:6]=[CH:5][C:4]=2[C:3]=1[F:23].[CH:24]1([S:27](Cl)(=[O:29])=[O:28])[CH2:26][CH2:25]1.C(OCC)(=O)C>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCCCCC>[CH:24]1([S:27]([IH:21][C:18]2[CH:19]=[CH:20][C:15]([N:11]3[C:10]4[C:2]([F:1])=[C:3]([F:23])[C:4]5[CH:5]=[CH:6][O:7][C:8]=5[C:9]=4[NH:13][C:12]3=[O:14])=[C:16]([F:22])[CH:17]=2)(=[O:29])=[O:28])[CH2:26][CH2:25]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: O=c1[nH]c2c3occc3c(F)c(F)c2n1-c1ccc(I)cc1F
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: O=c1[nH]c2c3occc3c(F)c(F)c2n1-c1ccc([IH]S(=O)(=O)C2CC2)cc1F
Temperature: 30 °C
Reaction time: 3 h
Yield: 50.1 %

Procedure:
TEA (0.062 mL, 0.4465 mmol) was added to a solution of 4,5-difluoro-3-(2-fluoro-4-iodophenyl)-1H-benzofuro[6,7-d]imidazol-2(3H)-one (I-32a: 0.064 g, 0.1488 mmol) in dry DCM (5 mL) at 0° C. This was followed by the addition of cyclopropanesulfonyl chloride (0.0331 g, 0.222 mmol) and catalytic amount of DMAP. The reaction mass was stirred for 3 hours at 20-40° C. The reaction was monitored by TLC (25% ethyl acetate in hexane). The reaction mass was concentrated under reduced pressure and the concentrate was extracted with ethyl acetate. The organic layer was washed with water, brine solution, dried over sodium sulphate and concentrated under reduced pressure to afford the crude compound. Purification by column chromatography on silica gel (20% ethyl acetate in hexane) afforded 40 mg of the product (50% yield). 1H NMR (CDCl3, 300 MHz): δ 7.77 (t, 2H), 7.65 (d, 1H), 7.29 (d, 1H), 6.99 (d, 1H), 3.31-3.38 (m, 1H), 1.62-1.74 (dd, 2H), 1.23-1.30 (m, 2H). LCMS: 93.99%, m/z=534.6 (M+1). HPLC: 96.34%
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:11](C(OCC2C=CC=CC=2)=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:3][C:2]=1[CH3:1]
Reactant: CCOC(=O)C(C(=O)OCc1ccccc1)c1ccc([N+](=O)[O-])c(C)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)Cc1ccc(N)c(C)c1
Reaction time: 2 h

Procedure:
Batch 2: ethyl phenylmethyl (3-methyl-4-nitrophenyl)propanedioate (35 g, 98 mmol) was taken up in Ethanol (500 ml) and subjected to a hydrogenation at atmospheric pressure using 10% palladium on carbon (3.13 g, 2.94 mmol). After 2 hours a sample was taken for analysis. The reservoir was refilled with hydrogen and the reaction continued overnight. The catalyst was removed by filtration through celite and fresh catalyst palladium on carbon (3.13 g, 2.94 mmol) was added to the reaction mixture. The reaction was put on again for 3 hours. After leaving the reaction mixture under these conditions for the weekend, it was combined with BATCH 1 reaction mixture (equivalent reaction mixture) and filtered through celite to give a colourless filtrate. This solution was concentrated to an oily solid (wt=31.9 g). To this mixture was added toluene (200 ml) and the mixture was filtered from an insoluble white gum (wt=0.65 g). The filtrate was passed down a silica gel Biotage 75 L chromatography column eluting with the following ethyl acetate/iso-hexane gradient mixture and collecting 400 ml fractions:
Reaction SMILES: [CH:1]([O:4][CH:5]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=1)[CH3:6])([CH3:3])[CH3:2].[OH-].[Li+].Cl>CO.O>[CH:1]([O:4][CH:5]([C:7]1[CH:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[CH:15][CH:16]=1)[CH3:6])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(C(C)OC(C)C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)OC(C)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 0.1 %

Procedure:
To the solution of methyl 4-(1-isopropoxyethyl)benzoate (161 mg, 0.73 mol) in methanol and water (50 mL/10 mL) was added lithium hydroxide (50 mg, 2.1 mmol), the solution was stirred at room temperature for 12 hours. Then the solution was acidified by hydrogen chloride (1 N/mol) pH to 6, extracted with dichloromethane (50 mL*3), evaporated the solvent to give 4-(1-isopropoxyethyl)benzoic acid (137 mg, 90%)
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=O.[N+]([O-])(O)=O.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=1[NH:28][C:29]([NH2:31])=[NH:30]>>[N+:25]([C:22]1[CH:23]=[CH:24][C:19]([CH3:18])=[C:20]([NH:28][C:29]2[N:31]=[C:5]([C:7]3[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=3)[CH:4]=[CH:3][N:30]=2)[CH:21]=1)([O-:27])=[O:26]
Reactant: Cc1ccc([N+](=O)[O-])cc1NC(=N)N
Reactant: CN(C)C=CC(=O)c1cccnc1
Solvent: O=[N+]([O-])O
Product: Cc1ccc([N+](=O)[O-])cc1Nc1nccc(-c2cccnc2)n1

Procedure:
In other aspects the invention provides a process for the preparation of N-(5-nitro-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine comprising: (a) reacting 2-methyl-5-nitroaniline with cyanamide in the presence of hydrochloric acid to obtain 1-(2-methyl-5-nitrophenyl)guanidine hydrochloride; (b) converting 1-(2-methyl-5-nitrophenyl)guanidine hydrochloride to 1-(2-methyl-5-nitrophenyl)guanidine nitrate; (c) condensing 3-acetylpyridine with N,N-dimethylformamide dimethyl acetal to obtain 3-(dimethylamino)-1-(3-pyridinyl)-prop-2-en-1-one; and (d) reacting 3-(dimethylamino)-1-(3-pyridinyl)-prop-2-en-1-one with 1-(2-methyl-5-nitrophenyl)guanidine nitrate to obtain N-(5-nitro-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine.
Reaction SMILES: S([O-])([O-])(=O)=O.CS[C:8]([NH2:10])=[NH2+:9].CSC(N)=[NH2+].O.[CH2:17]([O:24][NH2:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[CH2:17]([O:24][NH:25][C:8]([NH2:10])=[NH:9])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CSC(N)=[NH2+]
Reactant: NOCc1ccccc1
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CCO
Product: N=C(N)NOCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 30.0 g. (0.12 moles) of S-methylthiouronium sulfate in 200 ml. of H2O there is added a solution of 24.6 g. (0.20 moles) of benzyloxyamine in 250 ml. of 95% ethanol. The mixture is stirred for 72 hours at room temperature. The clear solution is heated at reflux for two hours under a stream of nitrogen. The solvents are removed in vacuo and the residue is treated with 300 ml. of isopropanol. The solid is removed by filtration and dissolved in 300 ml. of water. The solution is made basic with 90 ml. of 10% aqueous sodium hydroxide. The precipitate is collected, washed with water and dried to give benzyloxyguanidine, m.p. 104°-5° C.
Reaction SMILES: [CH3:1][O:2][CH2:3]C(Cl)=O.[CH3:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]=1[NH:18][CH:19]1[CH2:24][O:23][C:21](=[O:22])[CH2:20]1.N1C=CC=CC=1>ClCCl>[CH3:1][O:2][CH2:3][N:18]([CH:19]1[CH2:24][O:23][C:21](=[O:22])[CH2:20]1)[C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[CH:17][C:8]=1[CH3:7]
Reactant: Cc1ccc2ccccc2c1NC1COC(=O)C1
Reactant: COCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCN(c1c(C)ccc2ccccc12)C1COC(=O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 2.4 g (0.022 mol) sample of methoxyacetyl chloride was added dropwise to a solution of 5.5 g (0.022 mol) 3-(N-2-methylnaphth-1-ylamino)-gamma-butyrolactone and 1.7 g (0.022 mol) pyridine in 100 ml dichloromethane. The reaction mixture was stirred one hour at about 25° C. and then heated under reflux for 6 hours. After cooling overnight, the reaction mixture was washed successively with water, saturated sodium bicarbonate solution, water, dried over magnesium sulfate and evaporated under reduced pressure. The residue was chromatographed through a silica gel column. Elution with 25% acetone/75% petroleum ether gave 4.3 g of the product, m.p. 42°-46° C. The product is tabulated in Table C as Compound No. C-2.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([OH:3])=[O:2].[NH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19]>>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:15]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[C:8](=[O:10])[C:7]2=[CH:13][CH:14]=1)([OH:3])=[O:2]
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: NCCC(=O)O
Product: O=C(O)CCN1C(=O)c2ccc(C(=O)O)cc2C1=O
Yield: 100.1 %

Procedure:
4-carboxyphthalic anhydride (1.0 g, 0.0052 mol) and β-alanine (0.46, 0.0052 mol) were refluxed as above for 7 hours. Crystallisation of the product from EtOH yielded 1.37 g (78%) of 101 as a white solid: mp=240-242° C.; Rf0.77 (A): Rf0.67 (B): Rf0.33 (D): 1H NMR (DMSO-d6); MS m/z (rel intensity) 263 (14), 262 (100); IR (cm−1): 2800-3250 (OH), 1350 (C═CH), 2671 (C—H), 1777 (C═O), 1725 (C═O), 1705 (C═O), 1620 (C═C), 1452 (C═C), 1385(C—O), 1226 (C—O), 731 (C═CH). MS m/z (rel intensity) 263 (14), 262 (100).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1(B(O)O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F:16][C:17]1[C:18](I)=[CH:19][C:20](=[O:36])[N:21]([CH2:23][CH2:24][C@@:25]([CH3:35])([S:31]([CH3:34])(=[O:33])=[O:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:22]=1.O>O1CCOCC1.[Pd]>[F:16][C:17]1[C:18]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:19][C:20](=[O:36])[N:21]([CH2:23][CH2:24][C@@:25]([CH3:35])([S:31]([CH3:34])(=[O:32])=[O:33])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:22]=1
Reactant: CCOC(=O)[C@@](C)(CCn1cc(F)c(I)cc1=O)S(C)(=O)=O
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)[C@@](C)(CCn1cc(F)c(-c2ccccc2)cc1=O)S(C)(=O)=O
Temperature: 90 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
Pd EnCat™ (95 mg, 0.037 mmol) was added to a mixture of potassium carbonate (312 mg, 2.26 mmoll), phenylboronic acid (131 mg, 1.07 mmol), and ethyl (2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate (319 mg, 0.716 mmol) in dioxane:water (10 ml, 4:1) in a 20 mL vial equipped with a stir bar. The reaction was heated to 90° C. and allowed to stir overnight at that temperature. The reaction was allowed to cool to RT, filtered and the catalyst was washed with methanol (10 ml) and dichloromethane (10 ml). The filtrate was concentrated to afford a crude solid. The crude was purified via flash chromatography using an Analogix SF15-12 column and an eluant of ethyl acetate in heptane (50-100%) and methanol in ethyl acetate (0-5%) to afford the title compound as a yellowish white solid (250 mg, 64.8%). LC-MS m/z 396.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.23 (t, J=7.12 Hz, 3H) 1.62 (s, 3H) 2.15-2.32 (m, 1H) 2.53-2.66 (m, 1H) 3.16 (s, 3H) 3.89-4.06 (m, 2H) 4.07-4.26 (m, 2H) 6.50 (d, J=7.61 Hz, 0H) 7.20-8.12 (m, 6H).
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][C:4]#[CH:5].I[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>C(#N)C>[C:16]1([C:5]#[C:4][CH2:3][CH2:2][CH2:1][OH:6])[C:17]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: C#CCCCO
Reactant: Ic1cccc2ccccc12
Solvent: CC#N
Solvent: CCN(CC)CC
Product: OCCCC#Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.9 %

Procedure:
A solution of 0.59 g (7 mmol) of 4-pentyn-1-ol in 3 ml of acetonitrile is added dropwise under an argon atmosphere to a suspension of 1.78 g (7 mmol) of 1-iodonaphthalene, of 1.48 ml (10.5 mmol) of triethylamine, of 0.066 g (0.35 mmol) of cuprous iodide and of 0.147 g (0.21 mmol) of di(triphenylphosphine)palladium dichloride (Ph3P)2PdCl2 in 4 ml of acetonitrile. The mixture is stirred at ambient temperature for 3 hours, 4 g of silica are then added and the mixture is evaporated to dryness. The product is purified by chromatography on silica gel, elution being carried out with an 80/20 and then 60/40 mixture of cyclohexane and of ethyl acetate, to produce 1.22 g of product in the form of a yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:18]=[N:19][CH:20]=[C:21]([OH:23])[CH:22]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[Cl:16][C:17]1[CH:22]=[C:21]([O:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH:20]=[N:19][CH:18]=1
Reactant: Oc1cncc(Cl)c1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3cncc(Cl)c3)c2cc1OC
Temperature: 140 °C
Reaction time: 6 h
Yield: 81.6 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (245 mg), 3-chloro-5-pyridinol (277 mg), and 4-dimethylaminopyridine (377 mg) were suspended in o-dichlorobenzene (13 ml), and the mixture was stirred at 140° C. for 6 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous sodium hydroxide solution and water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give the title compound (283 mg, yield 81%).
Reaction SMILES: [NH2:1][N:2]1[CH:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:3]1[CH3:9].[C-:10]#[N:11].[Na+].[O:13]([CH2:20][CH:21]=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:9][CH:3]1[CH2:4][CH2:5][CH2:6][CH:7]([CH3:8])[N:2]1[NH:1][CH:21]([CH2:20][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]#[N:11]
Reactant: CC1CCCC(C)N1N
Reactant: [C-]#N
Reactant: O=CCOc1ccccc1
Agent: [Na+]
Product: CC1CCCC(C)N1NC(C#N)COc1ccccc1
Yield: 76.2 %

Procedure:
12.8 g of 1-amino-2,6-dimethylpiperidine, 5.4 g of sodium cyanide and 15.0 g of phenoxyacetaldehyde are reacted analogously to 8a). 20.8 g of 2-(2,6-dimethylpiperidino)amino-3-phenoxypropionitrile are obtained, which are employed in the following step without further purification