Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]([NH:13][CH3:14])=[O:12].CN1C[CH2:20][O:19][CH2:18]C1.C[OH:23]>>[CH3:14][NH:13][C:11]([C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:18]([O:19][CH3:20])=[O:23])[CH:3]=2)[NH:7][N:6]=1)=[O:12]
Reactant: CNC(=O)c1n[nH]c2ccc(Br)cc12
Reactant: CN1CCOCC1
Reactant: CO
Product: CNC(=O)c1n[nH]c2ccc(C(=O)OC)cc12
Temperature: 70 °C
Reaction time: 24 h
Yield: 61 %

Procedure:
To a solution of 5-bromo-N-methyl-1H-indazole-3-carboxamide (710 mg, 2.8 mmol) in anhydrous methanol (20 mL) was added 1,1′-bis(diphenylphosphino)ferrocene-palladium (II) dichloride dichloromethane complex (400 mg, 0.56 mmol) and N-methylmorpholine (565 mg, 5.60 mmol). The reaction vessel was evacuated and back filled with nitrogen three times. The vessel was then filled with 30 psi carbon monoxide. The reaction mixture was heated to 70° C., increasing the pressure within the vessel to 45 psi. The reaction was agitated at 70° C. for 24 hours. The reaction mixture was cooled to room temperature and was filtered through Celite, rinsing with methanol. The filtrate was concentrated and purification by flash column chromatography gave the title compound (410 mg, 61%) as a brown solid. 1H NMR (400 MHz, DMSO-d6, δ): 13.9 (s, 1 H), 8.88 (s, 1 H), 8.49 (d, J=4.8, 1 H), 7.95-7.98 (m, 1 H), 7.68-7.70 (m, 1 H), 3.88 (s, 3 H), 2.82 (d, J=4.8 Hz, 3 H).
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][O:8][CH2:9][C:10]([CH3:37])([CH3:36])[CH2:11][O:12][C:13]1[C:14]2[C:21]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[C:20]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:19][C:15]=2[N:16]=[CH:17][N:18]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([C:21]2[C:14]3[C:13]([O:12][CH2:11][C:10]([CH3:37])([CH3:36])[CH2:9][O:8][CH2:7][C:6]([OH:38])=[O:5])=[N:18][CH:17]=[N:16][C:15]=3[O:19][C:20]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:27][CH:26]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OCC(C)(C)COCC(=O)OC(C)(C)C)c23)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OCC(C)(C)COCC(=O)O)c23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Put 280 mg (0.54 mmol) (3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}-2,2-dimethylpropoxy)acetic acid tert.-butyl ester in 8 ml dichloromethane. Add 2 ml trifluoroacetic acid and stir for 1 h at RT. Then concentrate by evaporation and mix the residue with petroleum ether. Filter the solid on a frit with suction, and dry at high vacuum. 220 mg (88.1% of theor.) of the target compound is obtained.
Reaction SMILES: [CH:1]1([CH2:4][C:5]([C:9]2[CH:10]=[N:11][C:12]([CH:15]([F:17])[F:16])=[N:13][CH:14]=2)([CH3:8])[C:6]#[N:7])[CH2:3][CH2:2]1.N.O.OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O>CO.[Ni]>[CH:1]1([CH2:4][C:5]([C:9]2[CH:10]=[N:11][C:12]([CH:15]([F:16])[F:17])=[N:13][CH:14]=2)([CH3:8])[CH2:6][NH2:7])[CH2:3][CH2:2]1
Reactant: CC(C#N)(CC1CC1)c1cnc(C(F)F)nc1
Agent: [Ni]
Agent: N
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Solvent: O
Solvent: CO
Product: CC(CN)(CC1CC1)c1cnc(C(F)F)nc1
Yield: 98.7 %

Procedure:
A mixture of 3-cyclopropyl-2-(2-(difluoromethyl)pyrimidin-5-yl)-2-methylpropanenitrile (1 g, 4.2 mmol) and NH3.H2O (3 mL) in MeOH (20 mL) was hydrogenated with Raney Ni (1.5 g) under 50 Psi for 3 h. The reaction mixture was filtered and concentrated to give 3-cyclopropyl-2-(2-(difluoromethyl)pyrimidin-5-yl)-2-methylpropan-1-amine (1 g), which was used directly for next step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[N:12]1[C:16]([CH2:19][OH:20])([CH2:17][OH:18])[CH2:15][CH2:14][C:13]1=[O:21].[C:22](O)(=O)C.[CH2:26]([CH:28]([CH2:31][CH3:32])C=O)[CH3:27].C([BH3-])#N.[Na+]>ClCCl>[OH:20][CH2:19][C:16]1([CH2:17][OH:18])[N:12]([C:3]2[CH:4]=[CH:5][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:7][C:2]=2[N:1]([CH:28]([CH2:31][CH3:32])[CH2:26][CH3:27])[CH3:22])[C:13](=[O:21])[CH2:14][CH2:15]1
Reactant: COC(=O)c1ccc(N2C(=O)CCC2(CO)CO)c(N)c1
Reactant: CCC(C=O)CC
Reactant: CC(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Product: CCC(CC)N(C)c1cc(C(=O)OC)ccc1N1C(=O)CCC1(CO)CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.4 %

Procedure:
A suspension of 1-(2-amino-4-methoxycarbonylphenyl)-5,5-bis-(hydroxymethyl)pyrrolidin-2-one (0.1 g, 0.34 mmol) from Example 6 in 2 mL of dichloromethane was treated with acetic acid (0.1 g, 1.6 mmol), 2-ethylbutyraldehyde (0.065 g, 0.65 mmol) and sodium cyanoborohydride (0.035 g, 0.55 mmol). The resulting mixture was stirred at ambient temperature for 2 h. The reaction mixture was quenched with a saturated sodium bicarbonate solution (2 mL) and the mixture was extracted with ethyl acetate (3×25 mL). The combined organic layers were dried and concentrated to give 0.14 g of crude oil which was purified by chromatography (silica gel; 10% ethanol in ether) to yield 0.115 g (90%) of 5,5-bis-(hydroxymethyl)-1-{4-methoxycarbonyl-2-[(3-pentyl)methylamino]phenyl}pyrrolidin-2-one as white solid, mp 142-143° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([C:13]#[N:14])[C:7]2[CH:8]=[CH:9][NH:10][C:11]=2[CH:12]=1.Cl[C:16]1[C:21]([CH:22]([CH3:24])[CH3:23])=[C:20]([O:25][CH3:26])[N:19]=[C:18]([O:27][CH3:28])[N:17]=1>CN(C=O)C.CCOC(C)=O>[CH:22]([C:21]1[C:16]([N:10]2[C:11]3[CH:12]=[C:4]([CH3:3])[CH:5]=[C:6]([C:13]#[N:14])[C:7]=3[CH:8]=[CH:9]2)=[N:17][C:18]([O:27][CH3:28])=[N:19][C:20]=1[O:25][CH3:26])([CH3:24])[CH3:23]
Reactant: COc1nc(Cl)c(C(C)C)c(OC)n1
Reactant: Cc1cc(C#N)c2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1nc(OC)c(C(C)C)c(-n2ccc3c(C#N)cc(C)cc32)n1
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 42 %

Procedure:
NaH (148 mg, 1.1 eq.) was added to 6-methyl-1H-indole-4-carbonitrile (526 mg, 3.37 mmol) in 20 mL of DMF. After 5 minutes, 4-chloro-5-isopropyl-2,6-dimethoxy-pyrimidine was added to the reaction mixture. The reaction mixture was heated at 50° C. for 5 hours. The reaction mixture was diluted with EtOAc and washed with brine. The organic layer was concentrated and purified (silica gel, 0-80% EtOAC/hexane) to give a white solid (470 mg, 42%). LC-MS shows 337.2 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]([CH:7](O)[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[CH2:6])[CH3:2].[Cl:16][C:17]1[C:22]([NH2:23])=[C:21](I)[CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:3][C:4]([C:5]1[CH2:6][C:21]2[C:22](=[C:17]([Cl:16])[CH:18]=[CH:19][CH:20]=2)[NH:23][C:7]=1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[O:15])[CH3:2]
Reactant: Nc1c(Cl)cccc1I
Reactant: C=C(C(=O)OCC)C(O)c1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)C1=C(c2cccnc2)Nc2c(Cl)cccc2C1
Temperature: 70 °C
Yield: 86.9 %

Procedure:
A degassed mixture of 2-[(hydroxy)(pyridin-3-yl)methyl]acrylic acid ethyl ester (8.2 g, 39.6 mmol), 6-chloro-2-iodoaniline (10.0 g, 39.5 mmol), triethylamine (9 mL, 122 mmol) and palladium(II) acetate (300 mg) in acetonitrile (80 mL) was heated at 70° C. overnight. The mixture was cooled to room temperature and partitioned between ethyl acetate (200 mL) and water (100 mL). The aqueous layer was separated and the organic layer was washed with brine (50 mL), filtered, dried (phase separator) and concentrated in vacuo to give a crude solid. This was washed with a minimum of ice-cold diethyl ether to yield 8-chloro-2-(pyridin-3-yl)-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (10.8 g, 87%) as a white solid. δH (CDCl3) 8.73 (m, 2H), 8.04 (m, 1H), 7.66 (dd, J 7.9, 5.5 Hz, 1H), 7.18 (m, 1H), 7.05 (m, 1H), 6.94 (m, 1H), 6.29 (s, 1H), 3.99 (m, 4H), 1.04 (t, J 7.1 Hz, 3H). LCMS (ES+) 315.0 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:11][O:10]2)=[CH:5][CH:4]=1.[CH2:12]([NH2:15])[CH2:13][NH2:14].C(O)C>CO>[OH:10][CH:9]([C:6]1[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1)[CH2:11][NH:14][CH2:13][CH2:12][NH2:15]
Reactant: CSc1ccc(C2CO2)cc1
Reactant: NCCN
Solvent: CO
Solvent: CCO
Product: CSc1ccc(C(O)CNCCN)cc1
Reaction time: 16 h

Procedure:
2-(4-Methylthiophenyl)oxirane (37 g.) is added, over the course of 20 minutes and at 30° C., to a solution of ethylenediamine (75 cc.) in methanol (56 cc.). After 16 hours at 20° C., ethanol (250 cc.) is added; the precipitate which forms is filtered off. Distilled water (375 cc.) is added to the ethanol solution and the oily impurity which separates out is extracted with diisopropyl ether (200 cc.). After concentrating the aqueous ethanolic solution under reduced pressure, N-[2-hydroxy-2-(4-methylthiophenyl)ethyl]ethylenediamine (37.9 g.) is obtained in the form of an oil.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13]2[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:12]=2[N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH3:7].[CH2:15]([N:14]1[C:13]2[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:12]=2[N:11]=[C:10]1[C@@H:8]([NH2:7])[CH3:9])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](N)c1nc2ccc(F)cc2n1Cc1ccccc1
Product: N
Temperature: 25 °C
Reaction time: 1 h
Yield: 186.4 %

Procedure:
[(S)-1-(1-Benzyl-6-fluoro-1H-benzoimidazol-2-yl)ethyl]carbamic acid tert-butyl ester (0.88 g, 2.39 mmol) was dissolved in DCM (10 mL) and TFA (4 mL) was added dropwise. The pale green mixture was stirred at RT for 1 h, under an atmosphere of nitrogen. The resultant mixture was concentrated in vacuo and the residue passed down an Isolute® SCX-2 cartridge, eluting with DCM, MeOH and then 2M NH3 in MeOH solution to afford the title compound as a pale red gum (0.60 g, 93%). 1H NMR (CDCl3, 400 MHz): δ 7.69 (1H, dd, J=8.81, 4.80 Hz), 7.37-7.28 (3H, m), 7.09-7.95 (3H, m), 6.89 (1H, dd, J=8.75, 2.44 Hz), 5.54-5.34 (2H, m), 4.26 (1H, q, J=6.67 Hz), 1.54 (3H, d, J=6.61 Hz)
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH:15]([C:18]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]([CH3:27])[CH3:26])[C:19]=1[NH2:20])([CH3:17])[CH3:16].[CH3:28][C:29]([CH3:31])=O.C(O)(=O)C>ClCCCl>[CH:29]([NH:20][C:19]1[C:18]([CH:15]([CH3:17])[CH3:16])=[CH:24][CH:23]=[CH:22][C:21]=1[CH:25]([CH3:27])[CH3:26])([CH3:31])[CH3:28]
Reactant: CC(C)=O
Reactant: CC(C)c1cccc(C(C)C)c1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)Nc1c(C(C)C)cccc1C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.1 %

Procedure:
NaBH(OAc)3 (3.2 g, 15 mmol) was added into a solution of 2,6-diisopropylaniline (0.940 mL, 4.98 mmol), acetone (1.8 mL, 25 mmol) and acetic acid (0.57 mL, 10 mmol) in 1,2-dichloroethane (30 mL) at room temperature. After stirring at room temperature for 16 h, the reaction was quenched by adding 1M NaOH aq. solution (20 mL). The organic layer was extracted with CH2Cl2 (30 mL), and the volatiles were evaporated under reduced pressure. Column chromatography (silica gel, 20:1 hexane/ethyl acetate) gave the product (0.733 g, 66.8%). 1H NMR (300 MHz, CDCl3) δ 7.24-6.95 (m, 3H), 3.47-3.12 (m, 3H), 2.86 (br. s, 1H), 1.27 (d, J=7.0 Hz, 12H), 1.19 (d, J=6.4 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 142.4, 142.1, 123.6, 123.3, 51.6, 28.0, 24.5, 23.7. HRMS-ESI (m/z): [M+H]+ calcd for C15H26N, 220.2065; found, 220.2064.
Reaction SMILES: [Cl-].[NH2:2][N+:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1>C1(C)C(C)=CC=CC=1>[Cl-:9].[Cl:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([NH:2][N+:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:15])=[CH:12][CH:11]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: N[n+]1ccccc1
Agent: [Cl-]
Solvent: Cc1ccccc1C
Product: O=C(N[n+]1ccccc1)c1ccc(Cl)cc1
Yield: 97 %

Procedure:
1-Aminopyridinium chloride (104 parts) and p-chlorobenzoyl chloride (150 parts) were heated in xylene (750 parts) at 140° C. for 4 hours. The solid product was filtered off and recrystallised from n-butanol to give 1-(p-chlorobenzamido)pyridinium chloride (209 parts, 97% yield), melting point 241° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].COC1C([S:20][C:21]#[N:22])=CC(C)=C(O)C=1>>[CH3:1][C:2]1[CH:7]=[C:6]([S:20][C:21]#[N:22])[CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9]
Reactant: COc1cc(O)c(C)cc1SC#N
Reactant: Cc1cccc(C)c1O
Product: Cc1cc(SC#N)cc(C)c1O

Procedure:
Compound XXA was prepared from 2,6-dimethylphenol in a similar manner as described for compound 1B. 400 MHz 1H NMR (DMSO-d6) δ 8.96 (s, 1H), 7.22 (s, 2H), 2.13 (s, 6H).
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[N+:12]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1)([O-:14])=[O:13].[Cl-].[Li+].C(N(C(C)C)CC)(C)C.C(OC(C)C)(C)C>O1CCCC1.[Hg]>[N+:12]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19][CH:3]([C:2](=[O:1])[CH2:9][CH2:10][CH3:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: CCCC(=O)CC(=O)OCC
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: [Cl-]
Agent: [Hg]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)OC(C)C
Product: CCCC(=O)C(Cc1ccc([N+](=O)[O-])cc1)C(=O)OCC
Temperature: 25 °C
Yield: 73.5 %

Procedure:
127.7 g of ethyl 3-oxohexanoate are dissolved in 700 ml of tetrahydrofuran. 174.5 g of 4-nitrobenzyl bromide and 35 g of lithium chloride are added and the mixture is stirred at room temperature. 286 ml of diisopropylethylamine are then introduced dropwise, which causes a slight exothermic effect. The mixture is then stirred for 3 hours at room temperature and thereafter for 10 hours under reflux. The solvents are evaporated off under vacuum and the residue is taken up with water and then extracted with chloroform. The organic phase is separated after settling has taken place and then washed with dilute hydrochloric acid solution, dried over magnesium sulphate and evaporated under vacuum. The oily residue obtained is taken up with isopropyl ether and the crystals formed are filtered off. The mother liquors are concentrated under vacuum and the residue is heated to 130° C. at 20 mmol mercury in order to remove the residual starting materials. 174 g of ethyl 2-(4-nitrobenzyl)-3-oxohexanoate are thereby obtained in the form of an oil, which is used without further purification for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:16])[CH2:13][CH2:12][N:11]([CH2:14][CH3:15])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.ClC1C=C(C=CC=1)C(O)=[O:22]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:16])[CH2:13][CH2:12][N+:11]([O-:22])([CH2:14][CH3:15])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: CCN1CCC(O)(c2cc(F)cc(Cl)c2)C1
Solvent: ClCCl
Product: CC[N+]1([O-])CCC(O)(c2cc(F)cc(Cl)c2)C1
Yield: 64.9 %

Procedure:
3-(3-chloro-5-fluorophenyl)-1-ethylpyrrolidin-3-ol (0.65 g, 2.67 mmol) was dissolved in dichloromethane (30 ml) and m-chlorobenzoic acid (1.38 g, 8.01 mmol) was added in portions. The mixture was stirred at ambient temperature for 15 h after which about 75% of the solvent was evaporated. The resulting slurry was purified with flash chromatography on basic Al2O3 eluted with methanol. The methanol was evaporated and dichloromethane (50 ml) and aqueous sodium carbonate (10%, 50 mL) was added. The organic phase was dried (MgSO4) and evaporated to give the title compound (0.45 g). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 158-160° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:22]=[C:21]([N:23]4[CH2:27][CH2:26][C@@H:25]([CH2:28][NH2:29])[CH2:24]4)[C:20]4[C:15](=[N:16][CH:17]=[CH:18][N:19]=4)[CH:14]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.CCN(CC)CC.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C1COCC1>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:22]=[C:21]([N:23]4[CH2:27][CH2:26][C@@H:25]([CH2:28][NH:29][S:38]([CH3:37])(=[O:40])=[O:39])[CH2:24]4)[C:20]4[C:15](=[N:16][CH:17]=[CH:18][N:19]=4)[CH:14]=3)=[CH:9][CH:8]=2)[CH2:5][CH2:6]1
Reactant: CS(=O)(=O)Cl
Reactant: NC[C@@H]1CCN(c2nc(-c3ccc(N4CCOCC4)cc3)cc3nccnc23)C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NC[C@@H]1CCN(c2nc(-c3ccc(N4CCOCC4)cc3)cc3nccnc23)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under N2, to a solution of (S)-(1-(7-(4-morpholinophenyl)pyrido[4,3-b]pyrazin-5-yl)pyrrolidin-3-yl)methanamine (Compound 77, 51 mg, 0.13 mmol) and Et3N (0.04 mL, 0.26 mmol) in anhydrous THF (3 mL) was added MsCl (30 mg, 0.26 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 0.5 hour, then quenched with H2O and extracted with EtOAc. The combined extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography to afford the title compound. MS (m/z): 469 (M+H)+.
Reaction SMILES: P(Br)(Br)[Br:2].[C:5]1(/[C:11](=[CH:14]\[F:15])/[CH2:12]O)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C1(C)C=CC=CC=1>[C:5]1(/[C:11](=[CH:14]\[F:15])/[CH2:12][Br:2])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: BrP(Br)Br
Reactant: OC/C(=C/F)c1ccccc1
Solvent: Cc1ccccc1
Product: F/C=C(/CBr)c1ccccc1
Reaction time: 3 h
Yield: 176.3 %

Procedure:
A solution of phosphorous tribromide (227 mg) in toluene (2 ml) is slowly added to a solution of (E)-2-phenyl-3-fluoroallyl alcohol (305 mg) in toluene at about -5° so that the temperature does not rise above 0°. The cooling bath is removed and stirring is continued for 3 hours. The reaction mixture is then poured into saturated, aqueous potassium carbonate (20 ml). The mixture is extracted with ether, and the ether solution is washed with water and dried (MgSO4). Evaporation of solvent gives (E)-2-phenyl-3-fluoroallyl bromide (318 mg); colorless oil;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12]N[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1C=C2[C:24](=[CH:25][C:26]=1[O:27][CH3:28])[C:23](=[O:29])CCC2.[CH3:30][NH:31][CH3:32].C=O.CI.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[C:13]3[C:24](=[CH:25][C:26]([O:27][CH3:28])=[C:17]([O:16][CH3:15])[CH:12]=3)[C:23](=[O:29])[CH:10]([CH2:30][N:31]3[CH2:4][CH2:3][CH2:2][CH2:7][CH2:32]3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CNC
Reactant: COc1cc2c(cc1OC)C(=O)CCC2
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc2c(cc1OC)C(O)(c1ccc(Cl)cc1)CC(CN1CCCCC1)C2=O
Reaction time: 4 h

Procedure:
2 g. of 4-p-chlorophenylpiperidin-4-ol are dissolved in 30 ml. of DMF. 4.05 g. of 2-dimethylaminomethyl-6,7-dimethoxy-1-tetralone methiodide, obtainable by reacting 6,7-dimethoxy-1-tetralone with dimethylamine and formaldehyde and quaternizing the product with CH3I, and 1 g. of Na2CO3 are added and the mixture is stirred for 4 hours at 20° under N2. After the customary work up, 2-(4-p-chlorophenyl-4-hydroxypiperidinomethyl-6,7-dimethoxy-1-tetralone is obtained. Hydrochloride, m.p. 227°-228°.
Reaction SMILES: N1C=CC=CC=1.Cl.CN(C)CCCN=C=NCC.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[NH2:33])[CH:20]=1.[N:34]1([C:40]2[N:41]=[C:42]([CH2:47][C:48]([O-])=[O:49])[NH:43][C:44](=[O:46])[CH:45]=2)[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.[Na+]>CN(C)C=O>[N:34]1([C:40]2[N:41]=[C:42]([CH2:47][C:48]([NH:33][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[O:26][CH2:25][C:21]3[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=3)=[O:49])[NH:43][C:44](=[O:46])[CH:45]=2)[CH2:35][CH2:36][O:37][CH2:38][CH2:39]1
Reactant: Nc1ccccc1OCc1cccnc1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccccc1OCc1cccnc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 37.2 %

Procedure:
2 ml of pyridine, 300 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride and 366 mg of 2-(pyridin-3-ylmethoxy)phenylamine are added to a solution of 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of example 1, in 2 ml of N,N-dimethylformamide. The reaction mixture is stirred at ambient temperature for 20 hours, and then concentrated under reduced pressure. Water and ethyl acetate are added and the resulting mixture is thus stirred for 30 minutes. The precipitate formed is filtered off, and rinsed with water, ethyl ether and petroleum ether. The solid obtained is dried under vacuum. 150 mg of 2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]-N-[2-(pyridin-3-ylmethoxy)phenyl]acetamide are obtained in the form of a brown solid, the characteristics of which are the following:
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:31])[CH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20][CH2:21][F:22])[CH:16]=2)[CH:11]=[CH:10][C:9]=1[Cl:30])C.Cl>O1CCOCC1.CO.O>[C:26]([O:25][C:23]([N:19]([CH2:18][C:15]1[CH:16]=[C:17]2[C:12]([CH:11]=[CH:10][C:9]([Cl:30])=[C:8]2[CH2:7][C:6]([OH:31])=[O:5])=[CH:13][CH:14]=1)[CH2:20][CH2:21][F:22])=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: CCOC(=O)Cc1c(Cl)ccc2ccc(CN(CCF)C(=O)OC(C)(C)C)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N(CCF)Cc1ccc2ccc(Cl)c(CC(=O)O)c2c1
Temperature: 45 °C

Procedure:
A aqueous solution of NaOH (2 M, 0.59 ml, 1.17 mmol) was added at RT under an atmosphere of argon to a solution of (7-{[tert-butoxycarbonyl-(2-fluoro-ethyl)-amino]-methyl}-2-chloro-naphthalen-1-yl)-acetic acid ethyl ester (249 mg, 0.59 mmol) in dioxane (2.7 ml). The slightly turbid mixture is rendered clear by the addition of 6 drops of MeOH. After warming to 45° C. for 2.5 h, HPLC analysis indicated complete consumption of starting material. Removal of solvent yielded a residue, which was taken up in water. After acidification to pH 4 by the addition of 1 M HCl, the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The crude product was used directly in the next step. ES+-MS: 413.3, 415.5 [M+H+H2O]+. ES−-MS: 394.2, 396.2 [M−H]−.
Reaction SMILES: C(OC(=O)[NH:7][C@@:8]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:18][CH:17]=1)([CH3:13])[C@H:9]([OH:12])[CH2:10][CH3:11])(C)(C)C.[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32]>C(Cl)Cl>[NH2:7][C@:8]([CH3:13])([CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:20][CH:21]=1)[C@H:9]([OH:12])[CH2:10][CH3:11].[F:34][C:33]([F:36])([F:35])[C:31]([O-:37])=[O:32]
Reactant: CCCCCCCOc1ccc(CC[C@@](C)(NC(=O)OC(C)(C)C)[C@H](O)CC)cc1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCOc1ccc(CC[C@@](C)(N)[C@H](O)CC)cc1
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of {(1R,2R)-1-[2-(4-Heptyloxy-phenyl)-ethyl]-2-hydroxy-1-methyl-butyl}-carbamic acid tert-butyl ester (25 mg, 0.06 mMol) in CH2Cl2 (3 ml) is added TFA (0.3 ml). The solution is stirred at RT for 2 hours. After removing the solvent under reduced pressure, the residue is lyophilized from dioxane to give the title compound as its trifluoroacetate salt as a white, amorphous powder.