Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[C:15]([CH3:16])=[CH:14][C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH2:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][C@@H:24]([CH2:32][OH:33])[NH:23]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[C:15]([CH3:16])=[CH:14][C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:12]2)=[C:6]([C:7]([N:23]2[C@H:24]([CH2:32][OH:33])[CH2:25][C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:22]2)=[O:9])[CH:10]=1
Reactant: CCOC(=O)c1cc(C)n(-c2ccc(Br)cc2C(=O)O)n1
Reactant: OC[C@@H]1Cc2ccccc2CN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc(C)n(-c2ccc(Br)cc2C(=O)N2Cc3ccccc3C[C@H]2CO)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.1 %

Procedure:
To an ice cooled solution of 5-bromo-2-(3-(ethoxycarbonyl)-5-methyl-1H-pyrazol-1-yl)benzoic acid (45.0 g, 127.8 mmol) in DCM (450 mL) were added (S)-(1,2,3,4-tetrahydroisoquinolin-3-yl)methanol (20.8 g, 102.27 mmol), HATU (72.7 g, 191.2 mmol), DIPEA (55.7 mL, 319.6 mmol) followed by stirring at RT for 12 h. The reaction mixture was diluted with DCM (750 mL), washed with water (500 mL), brine (100 mL), dried over sodium sulphate and concentrated invacuo. The residue was purified on silica gel (100-200 mesh) to afford the title compound as a liquid 50 g (79%). Rf=0.44 (55% EtOAc in hexane); 1H NMR (400 MHz, DMSO-d6): δ 8.00-7.40 (m, 3H), 7.30-7.00 (m, 4H), 6.80-6.40 (m, 1H), 5.10-3.80 (m, 7H), 3.50-2.40 (m, 3H), 2.40-2.10 (m, 3H), 1.30-1.00 (m, 3H); ES-MS: m/z 498.2 (M+H).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2-].[Na+].C[N:17](C)C1C=CC=CC=1>>[NH2:17][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:9]=1
Reactant: c1ccc(Cc2ccccn2)cc1
Reactant: CN(C)c1ccccc1
Agent: [NH2-]
Agent: [Na+]
Product: Nc1cccc(Cc2ccccc2)n1

Procedure:
2-benzylpyridine (Aldrich, 2.5 g, 0.015 mole), sodium amide (780 mg, 0.02 mole) and N,N-dimethylaniline (25 mL) were refluxed overnight. The contents were allowed to cool and were partitioned between ether and water. The ether layer was dried (MgSO4) and concentrated in vacuo leaving an oil. The oil was purified by chromatography. The purified material was dissolved in 1N HCl, lyophilized, and triturated with EtOAc to give 2-amino-6-benzylpyridine as a white solid.
Reaction SMILES: [C:1]1([C@@H:7]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]([O:10][C@@H:11]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:26][CH2:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[OH:37])=[O:29]>CCOC(C)=O.C(#N)C>[Br-:26].[F:36][C:33]1[CH:34]=[CH:35][C:30]([C:28](=[O:29])[CH2:27][N+:13]23[CH2:14][CH2:15][CH:16]([CH2:17][CH2:18]2)[C@@H:11]([O:10][C:8](=[O:9])[C@@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:12]3)=[C:31]([OH:37])[CH:32]=1
Reactant: O=C(O[C@H]1CN2CCC1CC2)[C@H](Nc1ccccc1)c1ccccc1
Reactant: O=C(CBr)c1ccc(F)cc1O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)[C@H](Nc1ccccc1)c1ccccc1)C2)c1ccc(F)cc1O
Product: [Br-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.1 %

Procedure:
To a solution of (R)—((R)-quinuclidin-3-yl) 2-phenyl-2-(phenylamino)acetate (diastereomer 1 of I2) (100 mg, 0.30 mmol) in EtOAc (3 ml) and acetonitrile (2 ml), was added 2-bromo-1-(4-fluoro-2-hydroxyphenyl)ethanone (69.3 mg, 0.30 mmol), and the reaction was stirred at room temperature for 15 hours (UPLC-MS: complete conversion). The solvent was evaporated and the crude was triturated in i-Pr2O-EtOAc (1/1) to obtain (R)-1-(2-(4-fluoro-2-hydroxyphenyl)-2-oxoethyl)-3-((R)-2-phenyl-2-(phenylamino)acetoxy)-1-azoniabicyclo[2.2.2]octane bromide (154.0 mg, 91% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[C:21]([F:22])=[CH:20][C:19]([F:23])=[CH:18][C:17]=2[F:24])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[C:21]([F:22])=[CH:20][C:19]([F:23])=[CH:18][C:17]=1[F:24]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1n[nH]c(=O)c(-c2c(F)cc(F)cc2F)c1-c1ccc(Cl)cc1
Product: Cc1nnc(Cl)c(-c2c(F)cc(F)cc2F)c1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
4.00 g of 5-(4-chlorophenyl)-6-methyl-4-(2,4,6-trifluorophenyl)-2H-pyridazin-3-one and 20 ml of phosphorus oxychloride were mixed and stirred at 110° C. for 1 hour. The reaction mixture was cooled down to room temperature and concentrated under reduced pressure. To the residue was added ethyl acetate and ice water, and was separated to two layer. The organic layer was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate, then, concentrated under reduced pressure, to obtain 4.16 g of 3-chloro-5-(4-chlorophenyl)-6-methyl-4-(2,4,6-trifluorophenyl)pyridazine (hereinafter, referred to as compound (i) of the present invention).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([CH2:9][CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[O:8][C:4]=2[CH:3]=1.Cl[C:19]1[N:24]=[CH:23][C:22]([CH2:25][CH2:26][CH3:27])=[CH:21][N:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([CH2:9][CH:10]3[CH2:11][CH2:12][N:13]([C:19]4[N:24]=[CH:23][C:22]([CH2:25][CH2:26][CH3:27])=[CH:21][N:20]=4)[CH2:14][CH2:15]3)[O:8][C:4]=2[CH:3]=1
Reactant: CCCc1cnc(Cl)nc1
Reactant: Brc1ccc2nc(CC3CCNCC3)oc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1cnc(N2CCC(Cc3nc4ccc(Br)cc4o3)CC2)nc1
Temperature: 90 °C
Yield: 83.7 %

Procedure:
A mixture of 6-bromo-2-(piperidin-4-ylmethyl)benzo[d]oxazole (0.13 g, 0.440 mmol), 2-chloro-5-propylpyrimidine (0.083 g, 0.529 mmol), and K2CO3 (0.122 g, 0.881 mmol) in DMF (4.4 mL) was heated in 90° C. oil bath for 12 h. It was cooled to rt, quenched with H2O (5 mL), and extracted with EtOAc-Et2O (3×4 mL, 1:1 v/v). The combined organic layers were washed with H2O (3×4 mL) and brine (4 mL). The solvent was evaporated to afford crude product, which was purified by column chromatography (silica gel, hexanes-EtOAc gradient 0-60% EtOAc) to afford the desired product as a colorless oil (153 mg, 83% yield). 1H NMR (500 MHz, CDCl3) δ 8.14 (s, 2H), 7.66 (d, J=1.8 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.43 (dd, J=8.4, 1.8 Hz, 1H), 4.73 (d, J=13.4 Hz, 2H), 3.04-2.77 (m, 4H), 2.48-2.32 (m, 2H), 2.24 (s, 1H), 1.85 (d, J=12.6 Hz, 2H), 1.67-1.49 (m, 2H), 1.37 (ddd, J=25.0, 12.4, 4.2 Hz, 2H), 0.92 (t, J=7.3 Hz, 3H). LCMS (m/z)=415 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:17])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C([O-])([O-])=O.[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1>[CH3:17][C:6]1[C:5]2[C:9](=[CH:10][C:2]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[CH:3][CH:4]=2)[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]=1
Reactant: C1CNCCN1
Reactant: Cc1nn(-c2ccccc2)c2cc(Br)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: Cc1nn(-c2ccccc2)c2cc(N3CCNCC3)ccc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 6-bromo-3-methyl-1-phenyl-1H-indazole (1 g, 3.50 mmol, 1.00 equiv) in toluene (20 mL), piperazine (600 mg, 6.98 mmol, 2.00 equiv), Cs2CO3 (1.7 g, 5.21 mmol, 1.50 equiv), Pd(AcO)2 (20 mg, 0.09 mmol, 0.03 equiv), BINAP (20 mg, 0.03 mmol, 0.03 equiv). The resulting solution was stirred overnight at 100° C. in an oil bath. The resulting mixture was cooled, the solids were filtered out. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1). The resulting residue (300 mg) was purified by Prep-HPLC with the following conditions (AGILENT Pre-HPLC (UV-Directed)): Column, SunFire Prep C18, 5 um, 19*100 mm; mobile phase, water with 0.05% TFA and MeOH (10% MeOH up to 42% in 4 min, hold 42% in 3.5 min, up to 100% in 0.1 min, hold 100% in 1.4 min); Detector, UV 220NMnm to yield 3-methyl-1-phenyl-6-(piperazin-1-yl)-1H-indazole as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2O)=[N:6][C:7]=1[CH2:8][CH3:9].[O:23]1C2C(=CC=CC=2)C(NC2C(CC)=NC=C(CC)N=2)CC1>>[Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][CH:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[O:23][CH2:13][CH2:12]2)=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1cnc(CC)c(NC2CCOc3ccccc32)n1
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Product: CCc1nc(NC2CCOc3ccccc32)c(CC)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting N-(3,4-dihydro-2H-chromen-4-yl)-3,6-diethylpyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ) 7.28–7.21, 6.96–6.89, 5.26, 4.54, 4.29–4.22, 2.84, 2.57, 2.22, 1.32–1.24; HRMS (FAB) calcd for C17H20BrN3O+H 362.0868, found 362.0861.
Reaction SMILES: C([O:8][C:9](=[O:21])[C:10]1[C:15]([F:16])=[CH:14][CH:13]=[C:12]([N+:17]([O-:19])=[O:18])[C:11]=1[F:20])C1C=CC=CC=1.[OH-].[Na+].Cl>O1CCCC1.O>[F:20][C:11]1[C:12]([N+:17]([O-:19])=[O:18])=[CH:13][CH:14]=[C:15]([F:16])[C:10]=1[C:9]([OH:21])=[O:8]
Reactant: O=C(OCc1ccccc1)c1c(F)ccc([N+](=O)[O-])c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1c(F)ccc([N+](=O)[O-])c1F
Reaction time: 2 h
Yield: 56.8 %

Procedure:
To 2,6-difluoro-3-nitro-benzoic acid benzyl ester (47, 750 mg, 2.6 mmol) in 4 mL of tetrahydrofuran and 2 mL of water, sodium hydroxide (0.2 g, 5.0 mmol) is added and the reaction is stirred for 2 hours. The reaction is acidified with dilute hydrochloric acid and extracted with ethyl acetate. The organic layer is concentrated under vacuum to provide the desired compound (48, 300 mg).
Reaction SMILES: Cl.O.C[O:4][C:5]1[CH2:6][C:7]2[CH2:8][CH2:9][C@@H:10]3[C@@H:19]([C:20]=2[CH2:21][CH:22]=1)[CH2:18][CH2:17][C@@:15]1([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]1=[CH2:23].C(=O)(O)[O-].[Na+]>CO.CC(C)=O>[CH2:23]=[C:14]1[CH2:13][CH2:12][C@H:11]2[C@H:10]3[C@H:19]([CH2:18][CH2:17][C@:15]12[CH3:16])[C@@H:20]1[C:7](=[CH:6][C:5](=[O:4])[CH2:22][CH2:21]1)[CH2:8][CH2:9]3
Reactant: C=C1CC[C@H]2[C@@H]3CCC4=C(CC=C(OC)C4)[C@H]3CC[C@]12C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CO
Product: C=C1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]12C
Reaction time: 1 h

Procedure:
Con. hydrochloric acid (6.0 mL) and water (6.0 mL) were added to a solution of 17-methylenestra-2,5(10)-dien-3-yl methyl ether (15, 702.8 mg. 2.471 mmol) in methanol (6 mL) and acetone (20 mL). See Example 17. After stirring 1 h, sodium bicarbonate (7.50 g) was added cautiously. The mixture was concentrated under reduced pressure once effervescence had ceased and water (50 mL) was added. The mixture was extracted three times with 25 mL portions of methylene chloride. The combined organic extracts were washed with 50 mL of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 10 mL of methylene chloride and the combined filtrates were concentrated under reduced pressure. The product was purified by decolorization with charcoal, flash chromatography (20% ethyl acetate/hexanes on silica gel), and recrystallization from aqueous ethanol to give a white powder (302.8 mg. 1.120 mmol, 45%), m.p. 83-89° C. (NA-1994A-271)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](Br)[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.C([N:19]1[CH2:24][CH2:23][C:22](=O)[C:21]([CH3:27])([CH3:26])[CH2:20]1)C1C=CC=CC=1>>[ClH:1].[CH3:26][C:21]1([CH3:27])[CH:22]([C:4]2[C:5]3[O:9][CH:8]=[CH:7][C:6]=3[CH:10]=[C:2]([Cl:1])[CH:3]=2)[CH2:23][CH2:24][NH:19][CH2:20]1
Reactant: CC1(C)CN(Cc2ccccc2)CCC1=O
Reactant: Clc1cc(Br)c2occc2c1
Product: CC1(C)CNCCC1c1cc(Cl)cc2ccoc12
Product: Cl

Procedure:
Beginning with 5-chloro-7-bromobenzofuran and 1-benzyl-3,3-dimethyl-4-oxopiperidine, 0.23 gm of the title compound were prepared as an off-white solid essentially as described in EXAMPLE 27.
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:26]([CH2:27][CH2:28][CH3:29])[CH2:25][CH2:24][CH2:23][CH2:22][C:21]([C:30]([O:32]C)=[O:31])=[CH:20][C:19]=3[CH:34]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].O1CCCC1.[OH-].[Na+].Cl>O.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:26]([CH2:27][CH2:28][CH3:29])[CH2:25][CH2:24][CH2:23][CH2:22][C:21]([C:30]([OH:32])=[O:31])=[CH:20][C:19]=3[CH:34]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCCCN3CCC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCCCN3CCC)cc1
Temperature: 90 °C
Reaction time: 7 h
Yield: 52.5 %

Procedure:
To methyl 9-(4-(2-butoxyethoxy)phenyl)-1-propyl-2,3,4,5-tetrahydro-1H-1-benzoazonin-6-carboxylate (2.1 g) was incorporated with tetrahydrofuran (27 ml) and methanol (27 ml), followed by adding aqueous 1N sodium hydroxide solution (9 ml), and the mixture was stirred at 90° C. for 7 hours. After cooling to 0° C., water was added and the mixture was neutralized with 1N hydrochloric acid. After extracting with ethyl acetate, the organic layer was washed with saturated brine, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was recrystallized from hexane-ethyl acetate to give 9-(4-(2-butoxyethoxy)phenyl)-1-propyl-2,3,4,5-tetrahydro-1H-1-benzoazonin-6-carboxylic acid (1.07 g) as yellow crystals.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[O:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[N:19]([CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH:31](Br)[C:32]([O:34][CH3:35])=[O:33])=[CH:26][CH:25]=1)[CH3:20]>CN(C)C=O.O>[O:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[N:19]([CH2:21][CH2:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:30][CH:31]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:32]([O:34][CH3:35])=[O:33])=[CH:28][CH:29]=1)[CH3:20]
Reactant: COC(=O)C(Br)Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1
Reactant: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)Sc1ccccc1
Temperature: 25 °C

Procedure:
Thiophenol (0.92 mL) was added slowly to an ice-cooled, stirred suspension of sodium hydride (60% dispersion in oil, 0.38 g) in dry N,N-dimethylformamide (60 mL). The mixture was allowed to warm to room temperature over 30 minutes prior to the addition of a solution of methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-bromopropanoate (3.85 g) in N,N-dimethylformamide (40 mL) and the mixture was then heated at 80° C. for 72 hrs, cooled and diluted with water (1 L). The mixture was extracted with ethyl acetate (3×250 mL) and the combined organic solutions washed with water (3×1 L) and brine (1 L), dried (MgSO4) and evaporated. The residue was chromatographed on silica gel using a gradient of 1% methanol to 2% methanol in dichloromethane as eluent to afford the title compound, mp 78°-9° C. (dichloromethane-hexane).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][NH:6][CH2:7][CH3:8])[CH3:2].[C:9]1([CH:15](Cl)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:9]1([CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][NH:6][CH2:7][CH3:8])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCNCCNCC
Reactant: ClC(c1ccccc1)c1ccccc1
Product: CCNCCN(CC)C(c1ccccc1)c1ccccc1
Yield: 41.3 %

Procedure:
Reaction and treatment were carried out using 21 g of N,N'-diethylethylenediamine and 7.3 g of diphenylmethyl chloride in accordance with the same procedure as in Example 3-(a), in order to obtain 4.2 g of N-diphenylmethyl-N,N'-diethylethylenediamine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([NH2:10])[N:3]=1.C1C(=O)N([I:18])C(=O)C1.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[C:7]([I:18])=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([NH2:10])[N:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CCc1cc(Cl)nc(N)n1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Product: CCc1nc(N)nc(Cl)c1I
Temperature: 25 °C

Procedure:
25.0 g (159 mmol) 4-Chloro-6-ethyl-pyrimidin-2-ylamine in 1.0 L acetic acid is cooled to 0° C. and 36.0 g (159 mmol) NIS is added in one portion. The reaction mixture is stirred at RT until conversion of the starting material is completed (18 h). An aqueous solution of 5% Na2S2O3 and 10% NaHCO3 is added until the mixture decolorizes. The formed precipitate is filtered off, taken up with water and the suspension stirred at RT for 60 minutes. The product is filtered off, washed with diethyl ether and dried in vacuo at 40° C. Yield: 40.3 g (90%). 1H NMR (DMSO-d6) δ: 7.2 (s, 2H), 2.7 (quart., 2H), 1.1 (tripl., 3H). HPLC-MS: tR=1.62 min., (M+H)=284.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](/[CH:14]=[CH:15]/[C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24](O)=[O:25])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:28]([O:30][C:31](=[O:37])[CH2:32][C@@H:33]([C:35]#[CH:36])[NH2:34])[CH3:29].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[CH2:28]([O:30][C:31](=[O:37])[CH2:32][C@@H:33]([C:35]#[CH:36])[NH:34][C:24]([C@@H:20]1[CH2:21][CH2:22][CH2:23][N:18]([C:16](=[O:17])/[CH:15]=[CH:14]/[CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9][CH2:10]2)[CH2:19]1)=[O:25])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC(/C=C/C(=O)N2CCC[C@@H](C(=O)O)C2)CC1
Reactant: C#C[C@@H](N)CC(=O)OCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: C#C[C@H](CC(=O)OCC)NC(=O)[C@@H]1CCCN(C(=O)/C=C/C2CCN(C(=O)OC(C)(C)C)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.3 %

Procedure:
To a mixture of (R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)-(E)-acryloyl]-3-piperidinecarboxylic acid (1 g), 3(S)-ethynyl-β-alanine ethyl ester hydrochloride (0.48 g) and 1-hydroxybenzotriazole (0.37 g) in dimethylformamide (10 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.5 ml) at 0° C. The reaction mixture was stirred overnight at room temperature, and then poured into water. The whole was extracted with ethyl acetate, washed with aqueous saturated NaHCO3, water, and brine, dried over MgSO4, and evaporated in vacuo, subsequently. The residue was purified by column chromatography on silica gel eluting with CHCl3-MeOH (99:1) to give N-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)-(E)-acryloyl]-3-piperidylcarbonyl]-3(S)-ethynyl-β-alanine ethyl ester as a pale yellow oil (1.34 g).
Reaction SMILES: [CH2:1]=[CH:2][C@H:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].N1C=CC=CC=1.[F:16][CH:17]([C:21]([F:24])([F:23])[F:22])[C:18](Cl)=[O:19].O>ClCCl>[F:16][CH:17]([C:21]([F:24])([F:23])[F:22])[C:18]([O:9][CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH:2]=[CH2:1])=[O:19]
Reactant: C=C[C@H](O)CCCCC
Reactant: O=C(Cl)C(F)C(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CC(CCCCC)OC(=O)C(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
In 200 ml of dichloromethane were dissolved 28 g (0.22 mol) of (R)-(-)-1-octen-3-ol (92%ee) and 21 ml (0.26 mol) of pyridine, and then 39.5 g (0.24 mol) of 2,3,3,3-tetrafluoropropionyl chloride was dropwise added to the above-obtained solution while the solution was being cooled with ice. The resulting mixture was stirred at room temperature for 1 hour, subsequently water was added thereto, and then the reaction mixture was subjected to extraction with ether. The resulting extract was washed with 1N hydrochloric acid, a 5% aqueous solution of sodium hydrogencarbonate, and brine, and then dried with magnesium sulfate. Subsequently, the solvent was removed under reduced pressure, and the residual product was distilled at 95° C. under 25 mmHg, thereby obtaining 42.3 g of 1-octen-3-yl 2,3,3,3-tetrafluoropropionate in a yield of 76%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:10]([O-])=O)[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].C([O-])=O.[NH4+]>C1COCC1.CO.C(OCC)(=O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([NH2:10])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9]
Reactant: CSc1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CSc1ccc(N)cc1F
Yield: 71.9 %

Procedure:
10.0 g of 3-fluoro-4-methylsulfanylnitrobenzene prepared in the above example 1, 0.1 eq of Pd/C (5 wt %), 4 eq of amonium formate were dissolved in THF/MeOH (1:1) and refluxed for 3 hours. The solid, which was not dissolved in the solution, was filtered away, and the filtrate was distilled under reduced pressure to obtain oily compound, which was dissolved again in 80 ml of ethyl acetate. Solid amonium formate which was not dissolved in the solution, was filtered away, and the filtrate was distilled under reduced pressure to obtain oily filtrate, which was purified by column chromatography (ethyl acetate:n-Hexane=1:3) to give 6.04 g of the title compound as a yellow solid (yield 88%).
Reaction SMILES: CN([CH:4]=[O:5])C.O=P(Cl)(Cl)Cl.[ClH:11].[N:12]12[CH2:20][CH:16]([CH2:17][CH2:18][CH2:19]1)[C:15](=O)[CH2:14][CH2:13]2.C(=O)([O-])[O-].[K+].[K+]>>[Cl:11][CH:15]1[CH:16]2[CH2:20][N:12]([CH2:19][CH2:18][CH2:17]2)[CH:13]=[C:14]1[CH:4]=[O:5]
Reactant: CN(C)C=O
Reactant: O=C1CCN2CCCC1C2
Reactant: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Product: O=CC1=CN2CCCC(C2)C1Cl
Temperature: 100 °C
Yield: 91.6 %

Procedure:
To DMF (50 ml, 0.68 mol) was slowly added POCl3 (50 ml, 0.54 mol) at OOC over 1 h. 1-Azabicyclo[3.3.1]nonane-4-one hydrochloride (17.5 g, 0.1 mol) was added in one portion and the reaction mixture heated at 100° C. for 1 h. After cooling the reaction mixture was poured on ice (1000 g) and the reaction mixture neutralized with potassium carbonate. The water phase was extracted with ether (5×200 ml). The organic phase was dried over MgSO4 and evaporated. The residue was purified by column chromatography (eluent: CH2Cl2/CH3OH (9:1)), yielding 17 g of the title compound.
Reaction SMILES: [Br-:1].[C:2]1([PH+:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:22].[CH3:25]O>C1C=CC=CC=1>[Br-:22].[Br:1][CH2:25][P+:8]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CO
Reactant: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Reactant: BrP(Br)Br
Agent: [Br-]
Solvent: c1ccccc1
Product: BrC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of hydroxymethyl)triphenylphosphonium bromide and phosphorus tribromide in benzene is heated at reflux for 23 h with stirring. After this time the solution is dark orange and an orange solid is present The mixture is cooled to 25° C. and methanol is added. The solvent was removed at reduced pressure and the residue treated with water to extract the phosphonium salt. The aqueous extracts were saturated with solid potassium bromide and extracted with chloroform. The phosphonium salts are crystallized from hot chloroform by addition of ethyl acetate.