Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:12][CH2:13]Cl)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[CH3:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][C:23]#[N:24].[H-].[Na+]>C1COCC1.CN(C=O)C>[C:23]([C:22]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH3:15])[CH2:13][CH2:12][N:4]([C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH2:3][CH2:2]1)#[N:24]
Reactant: Cc1ccccc1CC#N
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1ccccc1C1(C#N)CCN(C(=O)OC(C)(C)C)CC1

Procedure:
A solution of bis(2-chloroethyl)-N-(1,1-dimethylethoxy)carbonyl amine (1.438 g, 5.94 mmol) and 2-methylphenyl acetonitrile (600 mg, 3.96 mmol) in a 4:1 mixture of THF/DMF (15 mL) was treated with NaH (357.9 mg, 8.7 mmol) at 60° C. (3 d). The solvent was removed in vacuo, the residue dissolved in EtOAc (200 ml) and washed with saturated NaHCO3 (50 ml), H20 (2×50 ml), and saturated aqueous NaCl (50 ml), dried (Na2SO4) and concentrated in vacuo. PCTLC (SiO2, 6mm, 100% hexane) afforded 4-cyano-N-(1,1-dimethylethoxy)carbonyl-4-(2-methylphenyl) piperidine as a yellow/orange oil.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:13])=[C:9]([CH:12]=1)[CH:10]=O)=[O:4].[CH3:14][C:15]([CH3:18])([NH2:17])[CH3:16]>CC(O)C>[Br:1][CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:13])=[C:9]([CH:10]=[N:17][C:15]([CH3:18])([CH3:16])[CH3:14])[CH:12]=1)=[O:4]
Reactant: O=Cc1cc(C(=O)CBr)ccc1O
Reactant: CC(C)(C)N
Solvent: CC(C)O
Product: CC(C)(C)N=Cc1cc(C(=O)CBr)ccc1O
Temperature: -3 °C
Yield: 74.7 %

Procedure:
5-(Bromoacetyl)-2-hydroxybenzaldehyde (109 g) is suspended in 2-propanol (920 ml) and cooled to -3° C. with stirring. The reaction mixture is treated with 1,1-dimethylethanamine (29.24 g) and stirred at -3° to 0° C. for 30 minutes whereupon precipitation occurs. The reaction mixture is allowed to warm to room temperature, stirred for 90 minutes then cooled to 10° C. and filtered. The solid obtained is washed with ice cold 2-propanol (2×100 ml) and dried in vacuo at 55° C. for 18 hours providing 89 g of 2-bromo-1-[3-[[(1,1-dimethylethyl)imino]methyl]-4-hydroxyphenyl]ethanone.
Reaction SMILES: [Si]([O:8][C@H:9]([C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[C:38]([CH2:43][OH:44])[CH:37]=1)[CH2:10][NH:11][C@H:12]([CH3:35])[CH2:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21]([NH:23][CH2:24][C:25]2[C:30]([O:31][CH3:32])=[CH:29][CH:28]=[CH:27][C:26]=2[O:33][CH3:34])=[O:22])[CH:17]=[CH:18][CH:19]=1)(C(C)(C)C)(C)C.C(O)(=O)C.[F-].[NH4+]>CO>[NH3:11].[CH3:34][O:33][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([O:31][CH3:32])[C:25]=1[CH2:24][NH:23][C:21](=[O:22])[CH2:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH2:13][C@H:12]([NH:11][CH2:10][C@H:9]([OH:8])[C:36]2[CH:41]=[CH:40][C:39]([OH:42])=[C:38]([CH2:43][OH:44])[CH:37]=2)[CH3:35])[CH:15]=1
Reactant: COc1cccc(OC)c1CNC(=O)Cc1cccc(C[C@@H](C)NC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(O)c(CO)c2)c1
Agent: [F-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1cccc(OC)c1CNC(=O)Cc1cccc(C[C@@H](C)NC[C@H](O)c2ccc(O)c(CO)c2)c1
Product: N
Temperature: 40 °C

Procedure:
A solution of 2-(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-N-(2,6-dimethoxybenzyl)-acetamide (Preparation 1) (125 mg, 0.20 mmol) in methanol (6 ml) was treated with acetic acid (6 ml) and ammonium fluoride (74 mg, 2.0 mmol) and the reaction heated to 40° C. for 16 hours. The solvent was removed in vacuo and the residue purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (95:5:0.5 changing to 93:7:0.7, by volume) to give the title compound as a white solid after trituration with diethyl ether (59 mg).
Reaction SMILES: ClC1C=C[C:5]([C:6](C2C=C(C=CN=2)C(NC2C=CC=CC=2)=O)=[O:7])=CC=1.[Cl:25][C:26]1([CH:40]=[CH:39][N:38]=[C:37]([C:41](=[O:48])[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:36]1)[C:27]([NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28].[CH2:49](N(CC)C1C=CC=CC=1)[CH3:50]>C(N(CC)CC)C>[CH2:49]([O:28][C:27]([O:7][CH2:6][CH3:5])([NH:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:26]1([Cl:25])[CH:40]=[CH:39][N:38]=[C:37]([C:41](=[O:48])[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:36]1)[CH3:50]
Reactant: O=C(Nc1ccccc1)c1ccnc(C(=O)c2ccc(Cl)cc2)c1
Reactant: CCN(CC)c1ccccc1
Reactant: O=C(C1=NC=CC(Cl)(C(=O)Nc2ccccc2)C1)c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(Nc1ccccc1)(OCC)C1(Cl)C=CN=C(C(=O)c2ccccc2)C1
Yield: 75 %

Procedure:
The procedure of Synthesis 1 was repeated except that 2-(4-chlorobenzoyl)-isonicotinanilide and triethylamine was replaced by 4-chloro-2-benzoyl-isonicotinanilide (11.2 g) and N,N-diethylaniline (15 ml), respectively. The titled compound was obtained in an amount of 10.3 g (yield: 75%). m.p. 133°-134° C.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH:7]([CH:8]([CH3:11])[CH2:9][OH:10])[O:6][C:5](=[O:12])[NH:4]1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.CCO[C:27]([CH3:29])=O>N1C=CC=CC=1>[CH3:23][C:13]1[CH:18]=[CH:17][C:16]([S:19]([O:10][CH2:9][CH:8]([CH:7]2[O:6][C:5](=[O:12])[NH:4][C@@H:3]2[CH2:2][O:1][S:19]([C:27]2[CH:29]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=2)(=[O:21])=[O:20])[CH3:11])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: CC(CO)C1OC(=O)N[C@@H]1CO
Reactant: CCOC(C)=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC(C)C2OC(=O)N[C@@H]2COS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Yield: 68 %

Procedure:
To a solution of (4R)-4-(hydroxymethyl)-5-(1-hydroxypropan-2-yl)oxazolidin-2-one (1.0 equiv.) in pyridine (0.15 M) at 0° C. was added p-toluenesulfonylchloride (2.1 equiv.). The solution was allowed to warm to rt as it stirred for 14 hours, at which time EtOAc was added and the solution was washed with H2O (3×), CuSO4(sat.) (2×), H2O, Na2CO3(sat.) and NaCl(sat.), dried over MgSO4, filtered, concentrated and purified by silica gel chromatography (75% EtOAc/hexanes eluent) yielding 2-((4R)-2-oxo-4-(tosyloxymethyl)oxazolidin-5-yl)propyl 4-methylbenzenesulfonate (68%). LCMS (m/z): 484.1 (MH+); LC Rt=4.06 min.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][C:21](=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:26][O:27][C:28](=[O:34])[CH2:29][CH2:30][CH2:31]CBr>>[ClH:19].[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[S:20][CH2:21][CH2:31][CH2:30][CH2:29][C:28]([O:27][CH3:26])=[O:34]
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Reactant: COC(=O)CCCCBr
Product: COC(=O)CCCCSc1c(Cl)ccc2c1CCNCC2
Product: Cl

Procedure:
Use a method similar to the Example 387 to react 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine with methyl-5-bromovalerate. Purify by preparative TLC eluting with 19:1 DCM/saturated ammonia in methanol. Use a method similar to the General Procedure 2-2 to give the title compound as a white solid. MS (APCI+) m/z: 328 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@H:6]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:5]2.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24]O)[CH:19]=1.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.[Cl:59]CCl>>[ClH:59].[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[CH2:7][C@H:6]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:5]3)[CH:19]=1
Reactant: ClCCl
Reactant: OCc1cccnc1
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(O)cc2C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(OCc3cccnc3)cc2C1
Product: Cl
Temperature: 25 °C

Procedure:
A mixture of N-[(2S)-5-hydroxy-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide (120 mg, 0.470 mmol, Description 3) and 3-pyridinylmethanol (51.3 mg, 0.470 mmol) in dichloromethane (10 ml) was stirred under argon at room temperature. Triphenylphosphine (123 mg, 0.470 mmol) and diisopropyl azodicarboxylate (0.091 ml, 0.470 mmol) were then successively added. The resulting mixture was stirred at room temperature under argon for 16 hours. The reaction mixture was washed with water, dried over sodium sulphate, filtered and evaporated. The desired product was purified by column chromatography on silica eluting with 1 to 99% ethyl acetate in n-pentane and then by SCX column eluting with 1M ammonia in methanol solution to give the title compound as a white solid. The free base solid was dissolved in methanol and treated with ethereal hydrochloride to give the HCl salt (64 mg).
Reaction SMILES: [OH:1][CH:2]([CH2:27][N:28]([CH3:30])[CH3:29])[CH2:3][O:4][C:5]1[CH:26]=[CH:25][C:8]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][CH2:17]3)[CH:13]=[CH:12][N:11]=2)=[CH:7][CH:6]=1.Cl[C:32]1N=C(N2C3C(=CC=CC=3)CCC2)C=CN=1>>[N:16]1([C:14]2[CH:13]=[CH:12][N:11]=[C:10]([NH:9][C:8]3[CH:7]=[CH:6][C:5]([O:4][CH2:3][CH:2]([OH:1])[CH2:27][N:28]([CH3:29])[CH3:30])=[CH:26][CH:25]=3)[N:15]=2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:32][CH2:18][CH2:17]1
Reactant: Clc1nccc(N2CCCc3ccccc32)n1
Reactant: CN(C)CC(O)COc1ccc(Nc2nccc(N3CCc4ccccc43)n2)cc1
Product: CN(C)CC(O)COc1ccc(Nc2nccc(N3CCCc4ccccc43)n2)cc1

Procedure:
Using an analogous method to that described in Example 1, but starting from 4-[2-hydroxy-3-(N,N-dimethylamino)propoxy]aniline hydrochloride (Method 1) and 2-chloro-4-(1,2,3,4-tetrahydroquinolin-1-yl)pyrimidine (Method 8), the product was obtained. NMR: 1.8-2.0 (m, 2H), 2.19 (s, 6H), 2.2-2.3 (m, 1H), 2.3-2.45 (m, 1H), 2.7-2.8 (m, 2H), 3.7-3.9 (m, 5H), 5.7 (m, 1H), 6.35 (m, 2H), 6.8 (m, 2H), 7.0-7.05 (m, 1H), 7.1-7.2 (m, 2H), 7.35-7.4 (m, 1H), 7.5-7.6 (m, 2H), 7.9-8.0 (m, 2H), 8.95 (s, 1H); MS (MH+): 420.5.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:39].[CH3:40][N:41]([CH3:47])[CH2:42][CH2:43][CH2:44][NH:45][CH3:46]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:45]([CH2:44][CH2:43][CH2:42][N:41]([CH3:47])[CH3:40])[CH3:46])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:39]
Reactant: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(S(C)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CNCCCN(C)C
Solvent: ClCCl
Product: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(N(C)CCCN(C)C)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 61.7 %

Procedure:
To a solution of 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide (15 mg, 0.027 mmol) in DCM (5 mL) was added N,N,N′-trimethyl-1,3-propanediamine (0.021 mL, 0.14 mmol). The resultant mixture was stirred at room temperature overnight. The mixture was concentrated under vacuo. Flash chromatography (90% CH2Cl2/7% MeOH/3% NH4OH) then provide the title compound (10 mg, 63%).
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.C(O)(=O)C.[NH:17]1[CH2:22][CH2:21][CH:20]([CH2:23][NH:24][C:25](=[O:27])[CH3:26])[CH2:19][CH2:18]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>O.CN(C)C(=O)C>[O:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4][CH:3]1[CH2:2][N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][NH:24][C:25](=[O:27])[CH3:26])[CH2:19][CH2:18]1
Reactant: BrCC1COc2ccccc2O1
Reactant: CC(=O)NCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(=O)NCC1CCN(CC2COc3ccccc3O2)CC1
Temperature: 75 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
A mixture of 12.6 parts of 2-(bromomethyl)-2,3-dihydro-1,4-benzodioxin, 11 parts of N-(4-piperidinylmethyl)acetamide acetate (1:1), 15 parts of sodium carbonate, 0.1 parts of sodium iodide and 135 parts of N,N-dimethylacetamide was stirred overnight at 75° C. The reaction mixture was poured into water. The product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was crystallized from a mixture of 1,1'-oxybisethane and 2,2'-oxybispropane. The product was filtered off and dried, yielding 3.2 parts (21.0%) of N-[[1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-4-piperidinyl]methyl]acetamide; mp. 137.9° C. (intermediate 89).
Reaction SMILES: [F:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([I:11])[C:3]=1[C:4]#[N:5].[N:12]1([CH2:18][CH2:19]O)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[F:1][C:2]1[C:9]([O:10][CH2:19][CH2:18][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=[C:6]([I:11])[C:3]=1[C:4]#[N:5]
Reactant: OCCN1CCOCC1
Reactant: N#Cc1c(I)ccc(O)c1F
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1c(I)ccc(OCCN2CCOCC2)c1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of Example 68A (250 mg, 0.95 mmol), 2-(4-morpholinyl)ethanol (0.19 mL) and triphenylphosphine on resin (630 mg, 3 mmol/g, 1.9 mmol) in THF (5 mL) was treated with DEAD (0.179 mL) and stirred at room temperature for about 18 hours. The mixture was filtered and the filtrate was concentrated. The residue was purified twice by flash column chromatography on silica gel, first eluting with 5% methanol/dichloromethane then with 50% ethyl acetate/hexanes to provide 180 mg of the desired product. MS (ESI(+)) m/e 377 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[CH2:7][C:6](=[N:22][OH:23])[C:5]1=[O:24].[CH2:25]([N:28]=[C:29]=[O:30])[CH2:26][CH3:27].C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][CH2:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[CH2:7][C:6](=[N:22][O:23][C:29]([NH:28][CH2:25][CH2:26][CH3:27])=[O:30])[C:5]1=[O:24]
Reactant: COCN1C(=O)C(=NO)CN(c2ccccc2F)c2ccccc21
Reactant: CCCN=C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCNC(=O)ON=C1CN(c2ccccc2F)c2ccccc2N(COC)C1=O
Yield: 85.2 %

Procedure:
1-Methoxymethyl-2-oxo-3-hydroxyimino-5-(2-fluorophenyl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (2.35 g) was dissolved in tetrahydrofuran (25 ml), propyl isocyanate (1.52 g) and triethylamine (1.81 g) were added thereto, and the mixture was refluxed for 3 hours. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (silica gel NH-DM1020, produced by Fujisilicia Co. Ltd., chloroform), to thereby obtain 2.52 g of the titled compound as brown amorphous (Yield: 85%).
Reaction SMILES: C([O:8][C:9]1[CH:25]=[CH:24][C:12]([C:13]([NH:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:14])=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)C.CO.C(Cl)Cl.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([NH:15][NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])=[O:14])=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)NNC(=O)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Solvent: CCO
Product: CC(C)(C)OC(=O)NNC(=O)c1ccc(O)cc1
Yield: 95.7 %

Procedure:
A solution of tert-butyl 2-[4-(benzyloxy)benzoyl]hydrazinecarboxylate (975 mg, 2.85 mmol) in presence of catalytic amount of Pd—C 10% in ethanol (40 mL) is hydrogenated for 3 hours. After filtration on celite, the residue is purified on column chromatography (silica gel, 10% MeOH in CH2Cl2) and tert-butyl 2-(4-hydroxybenzoyl)hydrazine carboxylate (0.688 g, yield: 96%) was identified by NMR spectroscopy.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([OH:14])=O)[CH:8]=[CH:7]2.[CH2:15]([NH2:21])[C:16]1[O:20][CH:19]=[CH:18][CH:17]=1.C(OP(C#N)(=O)OCC)C.C(N(CC)CC)C>CN(C=O)C>[O:20]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH2:15][NH:21][C:12]([C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([Br:1])[CH:3]=[N:4][CH:5]=2)[N:10]=1)=[O:14]
Reactant: O=C(O)c1ccc2cncc(Br)c2n1
Reactant: NCc1ccco1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCc1ccco1)c1ccc2cncc(Br)c2n1
Temperature: 25 °C
Reaction time: 26 h

Procedure:
8-Bromo-[1,6]naphthyridine-2-carboxylic acid (1) is stirred in DMF (20 mL) and furfurylamine (1 equiv.) is added. The reaction mixture is cooled to 0° C. (ice bath) and diethylcyanophosphonate (1 equiv.) is added followed immediately by triethylamine (2 equiv.). The reaction mixture is removed from the ice bath and stirred at room temperature for 26 hrs. The mixture is diluted with water (50 mL) and extracted with methylene chloride (3×50 mL). The combined organic layers are dried over sodium sulfate, filtered, and concentrated in vacuo to afford a tan solid, which is purified via silica gel chromatography (1:1; hexanes:EtOAc to 1:3.) LC/MS (M+H) 332.1.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][NH:8]C(=O)OC(C)(C)C)=[C:5]([C:18]([NH:20][CH3:21])=[O:19])[CH:4]=1>C(OCC)(=O)C>[Cl-:1].[F:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][NH3+:8])=[C:5]([C:18]([NH:20][CH3:21])=[O:19])[CH:4]=1
Reactant: CNC(=O)c1cc(F)ccc1CNC(=O)OC(C)(C)C
Reactant: Cl
Solvent: CCOC(C)=O
Product: CNC(=O)c1cc(F)ccc1C[NH3+]
Product: [Cl-]
Temperature: 25 °C

Procedure:
Hydrogen chloride gas was bubbled through a −78° C. solution of tert-butyl 4-fluoro-2-[(methylamino)carbonyl]benzylcarbamate (615 mg, 2.18 mmol) in ethyl acetate (20 mL) until the solution was saturated. The flask was then allowed to warm to room temperature. The reaction was concentrated in vacud to a volume of about 5 mL and the flask was capped and placed in the freezer overnight. In the morning, the solids that had precipitated were collected by vacuum filtration and washed with cold ethyl acetate to give the desired product as an off-white solid.
Reaction SMILES: [NH2:1][C@@H:2]([C:13]([NH:15][C@H:16]([C:29]([O:31][CH3:32])=[O:30])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[NH:33]([C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[C@H:34]([C:41](O)=[O:42])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[NH:33]([C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[C@H:34]([C:41]([NH:1][C@@H:2]([C:13]([NH:15][C@H:16]([C:29]([O:31][CH3:32])=[O:30])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)=[O:42])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C(N[C@H](C(=O)O)c1ccccc1)OCc1ccccc1
Reactant: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](N)Cc1c[nH]c2ccccc12
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H](NC(=O)OCc1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
17.0 g H-D-Trp-Lys(BOC)-OMe are mixed with 80 ml THF. 9.2 g Z-Phg-OH are added to the grey suspension at RT. Addition of 4.4 g HOBt, rinsing with 20 ml THF. The turbid yellow solution is cooled down to 0° and a solution of 5.3 ml DICI in 15 ml THF added within 10 minutes. Stirring 2 hours at 0°, then 2 hours at RT. Then addition of a solution of 3.6 sulfuric acid in 57 ml water, extraction with 70 ml ethyl acetate, washing with water, saturated brine, 5% sodium hydrogencarbonate, 25% brine, drying over MgSO4 and evaporation. The white residue is stirred in 125 ml isopropyl acetate 2 hours at 40° and the suspension filtered. Drying of the residue at 40°: slightly yellow substance. HPLC: 96.3% b.a. (25.3 min).
Reaction SMILES: [C:1]1([CH:7](O)[C:8]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.[H][H]>[Pd].O>[C:1]1([CH2:7][CH:8]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: CCCCCCC(=Cc1ccccc1)C(O)c1ccccc1
Agent: [Pd]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCC(Cc1ccccc1)Cc1ccccc1
Temperature: 50 °C
Yield: 61.2 %

Procedure:
In a 2-liter three-necked flask equipped with a stirring device and a nitrogen substituting device, 169.6 g of 1,3-diphenyl-2-n-hexyl-2-propen-1-ol, 0.4 milliliters of trifluoroacetic acid and 17 g of a Pd-C catalyst (a 5% product, containing 55.9% of water) were introduced, and stirred at 50° C. and contacted with hydrogen gas. After stirring for 30 hours, the catalyst was filtered off, water was added, and an extraction was carried out with n-heptane. After washing with sodium hydrogencarbonate and water, the solution was dried with anhydrous sodium sulfate. After removing off the solvent by a rotary evaporator and dissolving the residue in a small amount of n-heptane, a separating operation was carried out by a column chromatography with silica gel. By removing off the solvent again and carrying out a distillation under a decreased pressure, to obtain 98.9 g of 1,3-diphenyl-2-n-hexyl propane as colorless liquid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[CH:11]=[C:12]([O:19][CH2:20][CH2:21][O:22][CH3:23])[C:13]([N+:16]([O-])=O)=[N:14][CH:15]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].O>C(O)(=O)C.[Zn]>[CH3:1][S:2]([C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[CH:11]=[C:12]([O:19][CH2:20][CH2:21][O:22][CH3:23])[C:13]([NH2:16])=[N:14][CH:15]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: COCCOc1cc(Oc2ccc(S(C)(=O)=O)cc2)cnc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: COCCOc1cc(Oc2ccc(S(C)(=O)=O)cc2)cnc1N
Temperature: 105 °C
Yield: 96 %

Procedure:
5-(4-Methanesulfonyl-phenoxy)-3-(2-methoxy-ethoxy)-2-nitro-pyridine (0.39 mmol) is dissolved in acetic acid (4 ml). After addition of water (1.2 ml), zinc powder (6.3 eq.) is added and the reaction suspension is heated to 105° C. for 90 minutes. The reaction suspension is cooled to room temperature and filtrated. The filtrate is pored into 3.5% NaOH (30 ml) and extracted with dichloromethane. The combined organic layers are washed with brine, dried over MgSO4 and the solvent is removed in vacuo. 5-(4-Methanesulfonyl-phenoxy)-3-(2-methoxy-ethoxy)-pyridine-2-ylamine is obtained as yellow oil in a yield of 96%. HPLC (method C): 1.21 min, LC-MS (method A): 0.55 min, 339.15 (MO.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][C:6]1[C:11](=[O:12])[N:10]2[CH:13]=[CH:14][CH:15]=[C:16]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[C:21]([OH:28])[C:20]=3[CH2:29][CH2:30][CH3:31])[C:9]2=[N:8][CH:7]=1)C.[OH-].[Na+].Cl>C(O)C.O>[C:25]([C:22]1[CH:23]=[CH:24][C:19]([O:18][CH2:17][C:16]2[C:9]3=[N:8][CH:7]=[C:6]([CH2:5][C:4]([OH:32])=[O:3])[C:11](=[O:12])[N:10]3[CH:13]=[CH:14][CH:15]=2)=[C:20]([CH2:29][CH2:30][CH3:31])[C:21]=1[OH:28])(=[O:27])[CH3:26]
Reactant: CCCc1c(OCc2cccn3c(=O)c(CC(=O)OCC)cnc23)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCc1c(OCc2cccn3c(=O)c(CC(=O)O)cnc23)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.7 %

Procedure:
0.81 g (1.85 mmoles) of [9-(4-acetyl-3-hydroxy-2-n-propylphenoxymethyl)-4-oxo-pyrido[1,2-a]pyrimidin-3-yl]acetic acid ethyl ester and 20 ml (5.00 mmoles) of a 1% aqueous solution of sodium hydroxide were mixed with and dissolved in 30 ml of ethanol, and this mixture was stirred at room temperature for 3 hours. The resulting reaction solution was diluted with an appropriate amount of water and then neutralized with dilute hydrochloric acid. The solid matter which separated out was collected by filtration, washed with water and then dried. This precipitate was recrystallized from acetonitrile to obtain 0.59 g (78% yield) of [9-(4-acetyl-3-hydroxy-2-n-propylphenoxymethyl)-4-oxo-pyrido[1,2-a]pyrimidin-3-yl]acetic acid in the form of white crystals. These crystals had a melting point of 239°-243° C.