Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)=[CH:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[CH2:14][C:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(Cc2ccc3ccccc3n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C1=C(Cc2ccc3ccccc3n2)CCNC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
1-tert-Butoxycarbonyl-4-(2-quinolylmethyl)-1,2,5,6-tetrahydropyridine (1.98 g) was dissolved in dichloromethane (5 ml), and TFA (5 ml) was added to the solution under cooling on ice. The mixture was stirred for 2.5 hours at room temperature and concentrated under reduced pressure. A saturated solution of sodium hydrogencarbonate was added to the residue to neutralize, the mixture was then extracted with chloroform. The organic phase was dried over sodium sulfate anhydrate and concentrated under reduced pressure. The title compound was recovered from an ether-hexane solvent as white powder. This powder was also used for subsequent reaction without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)#[N:2].[ClH:12].[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.C(N(CC)CC)C>C(O)C.C(OCC)(=O)C>[ClH:12].[NH:2]=[C:1]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1
Reactant: N#Cc1ccc(C(=O)O)cc1
Reactant: C1CCNC1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: N=C(c1ccc(C(=O)O)cc1)N1CCCC1
Reaction time: 120 h

Procedure:
15.2 g (103 mmol) of 4-cyano-benzoic acid was added to 200 ml of an ethyl acetate solution containing 4 N hydrogen chloride and 50 ml of ethanol, and they were stirred for 5 days. The solvent was distilled off under reduced pressure, and 100 ml of ethyl acetate was added to the resulting solid, and the mixture was stirred for 30 minutes, and the solid was collected by filtration. The resulting solid was reacted with 15.0 g (211 mmol) of pyrrolidine and 10.0 g (98.8 mmol) of triethylamine for 2 days in 100 ml ethanol as the solvent. The solvent was distilled off, and 40 ml of 6 N hydrochloric acid was added to the residue, and it was reacted at 85° C. for 4 hours. The solvent was distilled off, and 50 ml of 1 N hydrochloric acid was added to the residue which was then stilled for 30 minutes, and the solid was collected by filtration and washed with 20 ml of ice-cold water. It was dried under reduced pressure to obtain the title compound.
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]([CH3:19])[NH:14][C:15](=[O:18])[NH:16][N:17]=2)=[CH:8][CH:7]=1.[OH-].[Na+].[ClH:22]>O>[ClH:22].[NH:5]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:13]([CH3:19])[NH:14][C:15](=[O:18])[NH:16][N:17]=2)=[CH:10][CH:11]=1)[NH2:1]
Reactant: CC1NC(=O)NN=C1c1ccc(N)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1NC(=O)NN=C1c1ccc(NN)cc1
Reaction time: 0.5 h

Procedure:
A solution of sodium nitrite (3.6 g) in water (10 ml) was added dropwise to a solution of 6-(4-aminophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (9.8 g), concentrated hydrochloric acid (10 ml) and water (30 ml) at 0° C. After stirring for 0.5 hours, a solution of stannous chloride dihydrate (43.12 g) in conc. hydrochloric acid (43 ml) was added thereto at 0° C. After stirring for 2 hours, the mixture was made alkaline with an aqueous solution of sodium hydroxide and the resultant precipitates were collected by filtration and washed with water. The crude product was dissolved in 10% hydrochloric acid under warming, and then allowed to stand at room temperature. The precipitates were collected by filtration and then dissolved in water. The aqueous solution was washed with ethyl acetate, treated with activated charcoal, and made alkaline with an aqueous solution of sodium hydroxide. The resultant precipitates were collected by filtration, washed with water, and recrystallized from 10% hydrochloric acid to give 6-(4-hydrazinophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one hydrochloride (3.2 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=1[N:19]=[C:20]=[O:21]>C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=1[NH:19][C:20]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2)=[O:21]
Reactant: O=C=Nc1c(Cl)cccc1Cl
Reactant: Nc1ccc2[nH]ncc2c1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc2[nH]ncc2c1)Nc1c(Cl)cccc1Cl
Temperature: 110 °C
Reaction time: 4 h

Procedure:
5-Aminoindazole (100 mg, 0.75 mmol) and 2,6-dichlorophenyl isocyanate (155.3 mg, 0.83 mmol, 1.1 eq) were dissolved in toluene, and the mixture was then stirred at 110° C. for 4 hr.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]([N:28]1[CH:31]([S:32][CH2:33][C:34](=O)[CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:30]([NH:43][C:44]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:29]1=[O:63])=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCOCC1>[CH2:35]([C:34]1[CH2:33][S:32][C@@H:31]2[CH:30]([NH:43][C:44]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)([C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)[C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:29](=[O:63])[N:28]2[C:8]=1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CC(C)(C)OC(=O)C(N1C(=O)C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1SCC(=O)Cc1ccccc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)C1=C(Cc2ccccc2)CS[C@@H]2C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N12
Yield: 62.7 %

Procedure:
1-(1-t-Butoxycarbonyl-1-triphenylphosphoranylidenemethyl)-3-(triphenylmethylamino)-4-(3-phenyl-2-oxopropylthio)azetidin- 2-one (331 mg) was refluxed in dry dioxan (15 ml) under nitrogen for 25 hours. Evaporation of the solvent and chromatography of the residue on silica gave (III) (141 mg). νmax (CHCl3) 3480, 1775, 1710, 1630 cm-1 δ ppm (CDCl3) 1.5 (s.9H), 2.95 (d.1H. J= 10Hz, D2O exchange), 3.00 (centre of AB quartet), 3.68 (centre of AB quartet, J= 15Hz), 4.25 (d. 1H. J= 5Hz), 4.70 (q. 1H, J= 5Hz, 10Hz, collapsing to a doublet, J= 5Hz, on D2O exchange), 7.1-7.7 (m, 20H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[NH:10][C:11]2[O:12][CH2:13][CH2:14][C@:15]([C:20]3[CH:25]=[C:24](Br)[CH:23]=[CH:22][C:21]=3[F:27])([CH:17]([F:19])[F:18])[N:16]=2)=[CH:5][CH:4]=1.C1(C)C=CC=CC=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.[C:79](=[NH:92])([C:86]1[CH:91]=[CH:90][CH:89]=[CH:88][CH:87]=1)[C:80]1[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[NH:10][C:11]2[O:12][CH2:13][CH2:14][C@@:15]([CH:17]([F:19])[F:18])([C:20]3[CH:25]=[C:24]([N:92]=[C:79]([C:80]4[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=4)[C:86]4[CH:91]=[CH:90][CH:89]=[CH:88][CH:87]=4)[CH:23]=[CH:22][C:21]=3[F:27])[N:16]=2)=[CH:5][CH:4]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: COc1ccc(C(NC2=N[C@@](c3cc(Br)ccc3F)(C(F)F)CCO2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc(C(NC2=N[C@@](c3cc(N=C(c4ccccc4)c4ccccc4)ccc3F)(C(F)F)CCO2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 105 °C
Reaction time: 4 h
Yield: 62.3 %

Procedure:
Under argon in a sealed tube were added to a solution of (S)—N-(bis(4-methoxyphenyl)(phenyl)methyl)-4-(5-bromo-2-fluorophenyl)-4-(difluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (intermediate E7.1) (725 mg, 1.16 mmol) in toluene (15 ml) sodium tert-butoxide (334 mg, 3.48 mmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (73.8 mg, 174 μmol) and tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (60.0 mg, 58.0 μmol) and benzophenone imine (420 mg, 389 μl, 2.32 mmol), the tube was sealed under argon and the mixture was stirred at 105° C. for 4 h. The brown solution was extracted with ethyl acetate/water. The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated to give a brown oil. The residue was chromatographed on 20 g silica gel with ethyl acetate 0-50% to give (S)—N-(bis(4-methoxyphenyl)(phenyl)methyl)-4-(difluoromethyl)-4-(5-(diphenylmethyleneamino)-2-fluorophenyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (525 mg, 723 μmol, 62.4% yield) as a yellow oil. MS (ISP): m/z=726.8 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:5]=1[C:6]([OH:8])=O)([O-:3])=[O:2].[NH2:16][C@H:17]([C:19]([OH:21])=[O:20])[CH3:18].C(=O)([O-])[O-].[Na+].[Na+]>>[N+:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]=1[C:6]([NH:16][C@@H:17]([CH3:18])[C:19]([OH:21])=[O:20])=[O:8])([O-:15])=[O:14]
Reactant: O=C(O)c1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: C[C@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C[C@H](NC(=O)c1c([N+](=O)[O-])cccc1[N+](=O)[O-])C(=O)O

Procedure:
As shown in scheme 1,2,6-dinitrobenzoyl chloride prepared from 2,6-dinitrobenzoic acid is treated with L-alanine in the presence of sodium carbonate to yield (S)-2-(2,6-dinitrobenzamido)propanoic acid (intermediate 13). Treatment of intermediate 13 either with K18F or K19F gave (S)-2-(2-fluoro-6-nitrobenzamido)propanoic acid, which on reduction with iron powder in the presence of acetic acid gave (S)-2-(2-amino-6-fluorobenzamido)propanoic acid (compound 12). In an analogous manner, treatment of 2,6-dinitrobenzoyl chloride with D-alanine gave (R)-2-(2,6-dinitrobenzamido)propanoic acid (intermediate 14), which on treatment either with K18F or K19F and further reduction with iron powder gave (R)-2-(2-amino-6-fluorobenzamido)propanoic acid (compound 13).
Reaction SMILES: [CH2:1]([C:5]1[C:6]([CH3:18])=[N:7][C:8]([Cl:17])=[N:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4].[Br:19]Br>CC(O)=O>[Br:19][CH2:18][C:6]1[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[C:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:9]=[C:8]([Cl:17])[N:7]=1
Reactant: BrBr
Reactant: CCCCc1c(C)nc(Cl)nc1-c1ccccc1
Solvent: CC(=O)O
Product: CCCCc1c(CBr)nc(Cl)nc1-c1ccccc1

Procedure:
A solution of the 5butyl-2-chloro-4-methyl-6-phenyl-pyrimidine (215 mg, 0.825 mmol) and Br2 (0.042 ml, 0.825 mmol) in AcOH (2 mL) is stirred at 80° C. for 21 hours. After cooling, the solution is concentrated. The residue is partitioned between Et2O and half saturated aqueous NaHCO3. The layers are separated, and the aqueous layer is reextracted once with Et2O. The combined extracts are dried over Na2SO4 and concentrated to 305 mg of crude 4-bromomethyl-5-butyl-2-chloro-6-phenyl-pyrimidine, which also contains small amounts of SM and dibromo material. This material is used without further purification.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[N:12][S:13][C:14]=2[C:15]([OH:17])=[O:16])=[CH:6][CH:5]=1.[CH2:18]([CH:20]1[O:22][CH2:21]1)Br.Cl>O>[O:22]1[CH2:21][CH:20]1[CH2:18][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[N:12][S:13][C:14]=2[C:15]([OH:17])=[O:16])=[CH:6][CH:5]=1
Reactant: BrCC1CO1
Reactant: O=C(O)c1snnc1-c1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1snnc1-c1ccc(OCC2CO2)cc1
Reaction time: 0.17 h

Procedure:
To a solution of 80 mg. of sodium hydroxide in 10 ml. of water is added 250 mg. of 4-(4-hydroxyphenyl)-5-carboxy-1,2,3-thiadiazole. The reaction mixture is stirred for 10 minutes and then treated dropwise with 0.4 ml. of epibromohydrin, maintaining the reaction mixture at room temperature under stirring for 48 additional hours. It is then acidified with 10% hydrochloric acid solution and extracted with ethyl acetate. The combined organic extracts are dried over sodium sulfate and evaporated to dryness under reduced pressure. Crystallization of the residue from chloroformmethanol affords the pure 4-[4(2,3-epoxypropoxy)phenyl]-5-carboxy-1,2,3-thiadiazole.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[F:5][C:6]1[CH:7]=[N:8][C:9](=[O:12])[NH:10][CH:11]=1>CS(C)=O>[CH3:1][NH:2][C:3]([N:10]1[CH:11]=[C:6]([F:5])[CH:7]=[N:8][C:9]1=[O:12])=[O:4]
Reactant: O=c1ncc(F)c[nH]1
Reactant: CN=C=O
Solvent: CS(C)=O
Product: CNC(=O)n1cc(F)cnc1=O
Yield: 60 %

Procedure:
Methylisocyanate (3.8 mmol) was added dropwise with vigorous stirring to a solution of 5-fluoropyrimidin-2-one (described in Undheim K. and Gacek M. Acta. Chem. Scand 23 (1969) 294) (2.5 mmol) in anhydrous DMSO (3.2 ml). The exothermic reaction started at once and a white solid was precipitated. The precipitate was collected after 50 minutes, washed with a little water, sucked dry, washed with ethyl acetate and dried; yield 60%, m.p. 166° C., 1H NMR (CDCl3): δ3.03 (N-Me), 8.66 (H-4), 8.71 (H-6).
Reaction SMILES: [CH2:1]([C:8]1[C:13](Br)=[CH:12][N:11]=[C:10]([CH2:15][CH2:16][CH:17]([OH:19])[CH3:18])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([C:22]1([OH:30])[CH:27]2[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]2)[CH2:23]1)#[CH:21].C(N(CC)CC)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN1CCCC1=O>[CH2:1]([C:8]1[C:13]([C:21]#[C:20][C:22]2([OH:30])[CH:27]3[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]3)[CH2:23]2)=[CH:12][N:11]=[C:10]([CH2:15][CH2:16][CH:17]([OH:19])[CH3:18])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(O)CCc1cc(Cc2ccccc2)c(Br)cn1
Reactant: C#CC1(O)CN2CCC1CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CC(O)CCc1cc(Cc2ccccc2)c(C#CC2(O)CN3CCC2CC3)cn1
Reaction time: 1 h
Yield: 58.1 %

Procedure:
50 mg of 4-benzyl-5-bromo-2-(3-hydroxybutyl)pyridine, 20 mg of 3-ethynyl-3-quinuclidinol, 20 mg of tetrakis(triphenylphosphine)palladium(0), 5 mg of cuprous iodide and 0.5 ml of triethylamine were added to 2 ml of 1-methyl-2-pyrrolidinone, followed by stirring for one hour in an oil bath kept at 110° C. After cooling as it was, it was evaporated. The residue was subjected to NH-silica gel column chromatography and eluted with 5% methanol/ethyl acetate, to give 30 mg of the target compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:27])=[C:6]([C@:8]23[CH2:16][O:15][C@H:14]([CH2:17][F:18])[C@H:13]2[CH2:12][S:11][C:10]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[N:9]3)[CH:7]=1.[CH3:28][O:29][C:30]1[N:31]=[CH:32][C:33]([C:36](O)=[O:37])=[N:34][CH:35]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.[PH4+]>C(Cl)Cl>[F:27][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:36]([C:33]2[CH:32]=[N:31][C:30]([O:29][CH3:28])=[CH:35][N:34]=2)=[O:37])=[CH:7][C:6]=1[C@:8]12[CH2:16][O:15][C@H:14]([CH2:17][F:18])[C@H:13]1[CH2:12][S:11][C:10]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[N:9]2
Reactant: COc1cnc(C(=O)O)cn1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(N)ccc3F)CO[C@H](CF)[C@H]2CS1
Agent: F[P-](F)(F)(F)(F)F
Agent: [PH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cnc(C(=O)Nc2ccc(F)c([C@]34CO[C@H](CF)[C@H]3CSC(NC(=O)OC(C)(C)C)=N4)c2)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 106.5 %

Procedure:
To a stirred solution of tert-butyl ((4aS,5S,7aS)-7a-(5-amino-2-fluorophenyl)-5-(fluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)carbamate (4.70 g) and 5-methoxypyrazine-2-carboxylic acid (2.65 g), in DCM (60 mL) was added N,N-diisopropylethylamine (8.0 mL) and (1H-benzotriazol-1-yloxy)tripyrrolidin-1-yl)phosphonium hexafluorophosphate (9.0 g, portionwise over 10 min). The reaction mixture was stirred at RT for 18 h, concentrated under vacuum to circa 20 mL, and sodium bicarbonate (sat., aq., 100 mL) was added. The mixture was extracted with EtOAc (2×150 mL), the combined organic portions were dried over MgSO4, evaporated and purified by silica gel chromatography (0% to 50% EtOAc in DCM gradient) to afford the title compound (6.71 g, approx. purity 90%) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.54 (m, 9H), 2.71-2.83 (br. s., 1H), 3.03-3.34 (br. s., 1H), 3.81-4.01 (br. s., 1H), 4.09 (m, 3H), 4.48-4.75 (m, 4H), 7.05-7.20 (m, 1H), 7.36-7.58 (m, 1H), 7.93-8.02 (m, 1H), 8.20 (d, J=1.3 Hz, 1H), 9.04 (d, J=1.3 Hz, 1H), 9.53 (br. s., 1H)
Reaction SMILES: CO.C([N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][CH2:18][OH:19])[CH:12]([C:20]([O:22][CH3:23])=[O:21])[CH2:11]1)C1C=CC=CC=1>[OH-].[Pd+2].[OH-].C(O)(=O)C>[C:20]([OH:22])(=[O:21])[CH3:12].[OH:19][CH2:18][CH2:17][CH2:16][CH:13]1[CH2:14][CH2:15][NH:10][CH2:11][CH:12]1[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)C1CN(Cc2ccccc2)CCC1CCCO
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)C1CNCCC1CCCO
Reaction time: 0.5 h

Procedure:
To 3 mL of a methanol solution containing 0.15 g of methyl 1-benzyl-4-(3-hydroxypropyl)piperidine-3-carboxylate, 0.12 mL of acetic acid and 0.15 g of palladium hydroxide were added, and the reaction mixture was stirred for 1 hour and 30 minutes under a hydrogen atmosphere. The insoluble material filtered off, and the solvent was removed under reduced pressure to obtain 0.12 g of a colorless oily substance, methyl 4-(3-hydroxypropyl)piperidine-3-carboxylate acetate. 1.34-1.41 (2H, m), 1.58-1.75 (4H, m), 1.87-1.95 (1H, m), 2.06 (3H, s), 2.80-2.90 (2H, m), 3.01 (1H, dd, J=3.7, 13.7 Hz), 3.20-3.28 (1H, m), 3.29-3.35 (1H, m), 3.65 (2H, t, J=6.3 Hz), 3.73 (3H, s)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18](O)=[O:19])[CH2:15][N:16]=1)=[CH:8]2.Cl.C(N=C=N[CH2:38][CH2:39][CH2:40][N:41](C)C)C.ON1C2C=CC=CC=2N=N1.C1(N)CC1>O.CN(C)C=O>[CH:40]1([NH:41][C:18](=[O:19])[CH2:17][CH:14]2[S:13][C:12]([C:9]3[NH:10][C:11]4[C:7]([CH:8]=3)=[CH:6][C:5]([O:21][C:22]3[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:26][CH:27]=3)=[CH:4][C:3]=4[O:2][CH3:1])=[N:16][CH2:15]2)[CH2:38][CH2:39]1
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Agent: Cl
Agent: NC1CC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)NC4CC4)S3)[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
A mixture of [2-(7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (200 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (120 mg), 1-hydroxybenzotriazole (90 mg) and N,N-dimethylformamide (3 mL) was stirred at room temperature for 30 min, and then cyclopropylamine (50 mg) was added to the mixture. The whole was stirred at room temperature for 15 h. Water was added to the mixture and the resultant was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residual crystals were washed with ethyl acetate-hexane and collected by filtration to give pale yellow crystals. The crystals were recrystallized from acetone-methanol to give the title compound (150 mg, 68%) as colorless prisms. MS 501 (MH+). mp 248-249° C.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]=[CH:27][CH3:28])[CH2:23][CH2:22][C:21]([C:29]([O:31]C)=[O:30])=[CH:20][C:19]=3[CH:33]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl>C1COCC1.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]=[CH:27][CH3:28])[CH2:23][CH2:22][C:21]([C:29]([OH:31])=[O:30])=[CH:20][C:19]=3[CH:33]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC=CCN1CCC(C(=O)OC)=Cc2cc(-c3ccc(OCCOCCCC)cc3)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC=CCN1CCC(C(=O)O)=Cc2cc(-c3ccc(OCCOCCCC)cc3)ccc21
Temperature: 40 °C
Reaction time: 6 h
Yield: 92.9 %

Procedure:
In THF (4.4 ml)/methanol (4.4 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-1-crotyl-2,3-dihydro-1-benzazepine-4-carboxylate (0.22 g). To the solution was added 1N sodium hydroxide solution (2.2 ml), and the mixture was stirred at 40° C. for 6 hours. pH was adjusted to approximate 5 with 1N hydrochloric acid, and the solvent was concentrated to half under reduced pressure. The concentrated material was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was washed with hexane/ethyl acetate=8/1) to give 7-[4-(2-butoxyethoxy)phenyl]-1-crotyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (198 mg).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].N=C1CC(C)CCN1.[NH2:13][C:14]1[CH:19]=[C:18]([CH2:20][CH2:21][CH3:22])[CH:17]=[CH:16][N:15]=1>>[C:1]([OH:4])(=[O:3])[CH3:2].[NH:13]=[C:14]1[CH2:19][CH:18]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:16][NH:15]1
Reactant: CCCc1ccnc(N)c1
Agent: CC1CCNC(=N)C1
Solvent: CC(=O)O
Product: CCCC1CCNC(=N)C1

Procedure:
The method of preparation of 2-imino-4-methylpiperidine acetate was used to convert 2-amino-4-(n-propyl)pyridine to the title compound except platinum oxide was used as the catalyst. Product was triturated with EtOAc to give a white solid. The analysis of the product was found to be consistent with the proposed structure. MH+=141; 1H NMR (D2O): δ3.35-3.05 (m, 2H); 2.60-2.40 (m, 1H); 2.15-2.00 (m, 1H); 1.80-1.60 (m, 2H); 1.78 (s, 3H); 1.35-1.05 (m, 5H); 0.75-0.65 (m, 3H).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1.C(N(CC)CC)C.CN(C=O)C>C(Cl)Cl>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([N:12]2[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: O=C1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CCC(=O)CC2)cc1
Reaction time: 8 h
Yield: 56.5 %

Procedure:
para-Toluenesulfonyl chloride (13.8 g, 72.2 mmol) was added to a suspension of 4-piperidone (10.1 g, 65.7 mmol) and triethylamine (7.30 g, 72.2 mmol) in CH2Cl2 (100 ml). After stirring at room temperature for 2 hours DMF (50 ml) was added to the reaction mixture and the stirring was continued overnight. The reaction mixture was concentrated in vacuo and saturated aqueous sodium bicarbonate was added to the residue. The resulting precipitate which formed was collected by suction filtration. The precipitate was washed with water followed by hexane and then dried under high vacuum to afford a white solid (9.4 g) which was used without further purification. 1H NMR (300 MHz, CDCl3) δ 7.69 (d, 2H, J=8.1 Hz), 7.34 (d, 2H, J=8.1 Hz) 3.39 (m, 4H), 2.55 (m, 4H), 2.44 (s, 3H).