Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:3]1.[CH3:33][S:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39]Cl)=[CH:37][CH:36]=1>>[CH3:33][S:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][O:1][CH:2]2[CH:7]([C:8]3[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:12][CH:13]=3)[CH2:6][CH2:5][N:4]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:3]2)=[CH:37][CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCOCCc3ccccc3)cc2)C(O)C1
Reactant: CSc1ccc(CCl)cc1
Product: CSc1ccc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCOCCc3ccccc3)cc2)cc1

Procedure:
In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-[4-(2-phenethyloxy-ethoxy)-phenyl]-piperidine-1-carboxylate with 4-methylthio-benzyl chloride [J.Org.Chem. (1988),53(3),561-569] there was obtained tert-butyl (3RS,4RS)-3-(4-methylsulphanyl-benzyloxy)-4-[4-(2-phenethyloxy-ethoxy)-phenyl]-piperidine-1-carboxylate as a colourless oil; MS: 578 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[N:7]([CH3:8])[CH2:6][CH2:5][N:4]2[N:9]=[C:10]([NH2:12])[CH:11]=[C:3]12.[C:13]([O:16][CH2:17][C:18]1[C:19]([N:33]2[CH2:44][CH2:43][N:42]3[C:35](=[CH:36][C:37]4[CH2:38][C:39](C)([CH3:45])[CH2:40][C:41]=43)[C:34]2=[O:47])=[N:20][CH:21]=[CH:22][C:23]=1[C:24]1[CH:29]=[C:28](Br)[C:27](=[O:31])[N:26]([CH3:32])[CH:25]=1)(=[O:15])[CH3:14].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>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.[Pd].[Pd].O1CCOCC1>[C:13]([O:16][CH2:17][C:18]1[C:19]([N:33]2[CH2:44][CH2:43][N:42]3[C:41]4[CH2:40][CH2:39][CH2:45][CH2:38][C:37]=4[CH:36]=[C:35]3[C:34]2=[O:47])=[N:20][CH:21]=[CH:22][C:23]=1[C:24]1[CH:29]=[C:28]([NH:12][C:10]2[CH:11]=[C:3]3[CH:2]([CH3:1])[N:7]([CH3:8])[CH2:6][CH2:5][N:4]3[N:9]=2)[C:27](=[O:31])[N:26]([CH3:32])[CH:25]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)OCc1c(-c2cc(Br)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: CC1c2cc(N)nn2CCN1C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCN(C)C4C)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
A 25-mL round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 287i (20 mg, 1.0 eq., 0.12 mmol), (4-(5-bromo-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)pyridin-3-yl)methyl acetate 273a (127 mg, 2.0 eq., 0.24 mmol), Pd2(dba)3 (9.0 mg, 0.1 eq., 0.010 mmol), Xantphos (11 mg, 0.2 eq., 0.020 mmol), Cs2CO3 (78 mg, 2.0 eq., 0.24 mmol), and dioxane (5 mL). After three cycles of vacuum/N2 flush, the mixture was stirred at 100° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica-gel column chromatography eluting with 20:1 dichloromethane/methanol to afford 287j as a brown solid (60 mg, 82%). MS-ESI: [M+H]+ 610.9
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](O)=[CH:6][CH:7]=[N:8]2.O=P(Cl)(Cl)[Cl:18]>C1(C)C=CC=CC=1>[Cl:18][C:5]1[C:4]2[C:9](=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:3]=2[O:2][CH3:1])[N:8]=[CH:7][CH:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc(OC)c2c(O)ccnc2c1
Solvent: Cc1ccccc1
Product: COc1cc(OC)c2c(Cl)ccnc2c1

Procedure:
To a mixture of crude 5,7-dimethoxyquinolin-4-ol (5.36 g, 26 mmol) and Hunig'sBase (9.1 ml, 52 mmol) in toluene, was added POCl3(29 ml, 313 mmol). The mixture was refluxed for 5 h. Excess POCl3 was removed under reduced pressure and azeotroped with toluene. The resultant gum was treated with sat. NaHCO3 until no gas generated. The mixture was extracted with EtOAc, the organic extracts were combined and washed with sodium bicarbonate and solvent removed under reduced pressure. The crude product was purified via column chromatography on silica gel (RediSep 120 g column, gradient elution with 0-50% EtOAc/DCM) to afford 4-chloro-5,7-dimethoxyquinoline as a yellow solid. MS Found m/z=[M+H]+. 224.2 Calc'd for C11H10ClN: 223.7.
Reaction SMILES: [Si:1]([O:8][CH:9]([CH:11]1[CH:14]([S:15][CH3:16])[N:13]([CH:17](Cl)[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[O:19])[C:12]1=[O:32])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[I-].[Na+].C([BH3-])#N.[Na+]>>[Si:1]([O:8][CH:9]([CH:11]1[CH:14]([S:15][CH3:16])[N:13]([CH2:17][C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=2)=[O:19])[C:12]1=[O:32])[CH3:10])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CSC1C(C(C)O[Si](C)(C)C(C)(C)C)C(=O)N1C(Cl)C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [BH3-]C#N
Agent: [I-]
Agent: [Na+]
Product: CSC1C(C(C)O[Si](C)(C)C(C)(C)C)C(=O)N1CC(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 66.2 %

Procedure:
Following the procedure of Preparation 3, but using p-nitrobenzyl 2-[3-(1-t-butyldimethylsilyloxyethyl)-4-methylthio-2-azetidinon-1-yl]-2-chloroacetate (1.272 g), sodium iodide (379 mg) and sodium cyanoborohydride (314 mg) and purifying the crude product by silica gel column chromatography eluted with a 10:1 by the volume mixture of benzene and ethyl acetate, there were obtained 785 mg of the desired compound.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13](=[O:26])[C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[N:16][CH:15]=3)[CH:10]=2)[CH:5]=[CH:4]1)[CH3:2].Br[C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][C:29]=1[F:37].C(C1C=C(NC(C2C=CC(N3CCN(C4C=CC(C(O)=O)=CC=4)CC3)=C(F)C=2)=O)C=CC=1)(C)(C)C>>[F:37][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][C:28]=1[N:23]1[CH2:24][CH2:25][N:20]([C:17]2[CH:18]=[CH:19][C:14]([C:13](=[O:26])[NH:12][C:9]3[CH:10]=[C:11]4[C:6]([CH:5]=[CH:4][N:3]4[CH2:1][CH3:2])=[CH:7][CH:8]=3)=[CH:15][N:16]=2)[CH2:21][CH2:22]1)[C:32]([OH:34])=[O:33]
Reactant: O=C(O)c1ccc(Br)c(F)c1
Reactant: CCn1ccc2ccc(NC(=O)c3ccc(N4CCNCC4)nc3)cc21
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)c(F)c2)c1
Product: CCn1ccc2ccc(NC(=O)c3ccc(N4CCN(c5ccc(C(=O)O)cc5F)CC4)nc3)cc21

Procedure:
3-fluoro-4-{4-[5-(1-ethyl-1H-indol-6-ylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid was synthesized from N-(1-ethyl-1H-indol-6-yl)-6-piperazin-1-yl-nicotinamide and 4-bromo-3-fluoro-benzoic acid in a manner similar to the one described in the synthesis of 4-{4-[4-(3-tert-butyl-phenylcarbamoyl)-2-fluoro-phenyl]-piperazin-1-yl}-benzoic acid above. LCMS calcd for C27H26FN5O3 (m/e) 487, obsd 488 (M+H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([F:12])[CH:5]=1)=O.Cl.[N+:14]([C:17]1[CH:25]=[CH:24][C:20]([CH2:21][O:22][NH2:23])=[CH:19][CH:18]=1)([O-:16])=[O:15].N1C=CC=CC=1>C(O)C>[N+:14]([C:17]1[CH:18]=[CH:19][C:20]([CH2:21][O:22][N:23]=[C:2]([C:4]2[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([F:12])[CH:5]=2)[CH3:1])=[CH:24][CH:25]=1)([O-:16])=[O:15]
Reactant: COc1ccc(C(C)=O)cc1F
Reactant: NOCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: COc1ccc(C(C)=NOCc2ccc([N+](=O)[O-])cc2)cc1F
Temperature: 25 °C
Yield: 65.3 %

Procedure:
A solution of 3-fluoro-4-methoxyacetophenone (0.064 g, 0.380 mmol), O-(4-nitrobenzyl)hydroxylamine hydrochloride (0.111 g, 0.552 mmol) and pyridine (0.14 ml, 1.73 mmol) in ethanol (7 ml) was stirred at reflux under nitrogen for 4 h and cooled to room temperature. The solution was concentrated to a yellow oil which was diluted with water/dichloromethane. The suspension was extracted with dichloromethane (×3). The combined organic phases were washed with water and brine, dried over magnesium sulphate, filtered and concentrated to a yellow oil. The crude product was purified by column chromatography (SiO2), eluting with 9:1 petrol/ethyl acetate, to give a yellow oil which was triturated with petrol, and the resultant off white solid was further washed with petrol to give 3′-fluoro-4′-methoxyacetophenone-O-4-nitrobenzyloxime (CP9-123) as a white solid (0.079 g, 65%), m.p. 67-68°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([CH:22]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(=[O:21])[CH3:20]>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH:17]=[CH:20][C:19](=[O:21])[CH3:22])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CCCc1ccc(OCc2ccccc2)cc1
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CC(=O)C=CCCc1ccc(OCc2ccccc2)cc1
Yield: 105.5 %

Procedure:
A solution of 21.2 g of 3-(p-benzyloxyphenyl)propionaldehyde and 30.9 g of acetylmethylenetriphenylphosphorane in 120 ml of tetrahydrofuran was heated under reflux for 4.5 hours, the solvent was then evaporated and the residual crystals were recrystallized from a mixture of n-hexane and ether (5:1) to give 26.1 g of the desired compound melting at 70°-72° C.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C([O-])C.[Na+].C(O)C.Br[CH2:24][CH2:25][CH2:26][CH2:27][Cl:28]>C(OCC)(=O)C.CO>[Cl:28][CH2:27][CH2:26][CH2:25][CH2:24][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:14][CH:15]=1
Reactant: ClCCCCBr
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1)c1ccc(OCCCCCl)cc1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
Combine 4-hydroxybenzophenone (347 g, 1.75 mol) and methanol (3.5 L). Heat to 50° C. and add a solution of sodium ethanolate in ethanol (718 mL, 21% by weight, 1.92 mol) over 20 minutes. Heat to reflux and add 1-bromo-4-chlorobutane (600 g, 3.5 mol) over 30 minutes. After 18 hours, cool the reaction mixture and evaporate in vacuo to obtain a residue. Add ethyl acetate (5 L) to give a solid. Filter and extract the filtrate with aqueous 10% sodium hydroxide solution and aqueous saturated sodium chloride solution. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give 4-(4-chlorobutoxy)benzophenone.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:18]=2)[CH2:9][CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[F:37][C:38]1[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=1>ClCCl>[F:37][C:38]1[CH:43]=[CH:42][C:41]([S:44]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([N:8]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:28])([F:29])[CH:25]([F:26])[F:27])[CH:18]=3)[CH2:9][CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12])[CH:3]=2)(=[O:46])=[O:45])=[CH:40][CH:39]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: Nc1cccc(N(Cc2cccc(OC(F)(F)C(F)F)c2)CC(O)C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(Nc1cccc(N(Cc2cccc(OC(F)(F)C(F)F)c2)CC(O)C(F)(F)F)c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 29 %

Procedure:
The 3-[(3-aminophenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol from EX-528C (50 mg, 0.12 mmol) was dissolved in 1 mL of dichloromethane. Triethylamine (25 μL, 0.18 mmol) followed by 4-fluorobenzene-sulfonyl chloride were added. The solution was stirred at room temperature for 5 hours, at which time HPLC analysis indicated that no free amine starting material remained. The reaction was quenched with water and filtered through pre-wetted celite eluting with ethyl acetate. The solvent was evaporated, and the residue was purified by reverse phase HPLC eluting with 10% to 90% acetonitrile in water to afford 20.1 mg (29%) of the desired 4-fluoro-N-[3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-(3,3,3-trifluoro-2-hydroxypropyl)amino]phenyl]benzenesulfonamide product as a yellow oil, which was greater than 98% pure by reverse phase HPLC analysis. HRMS calcd. for C24H21F8N2O4S: 585.1094 [M+H]+, found: 585.1083. 1H NMR (CDCl3) δ3.6 (m, 2H), 3.8 (dd, 1H), 4.3 (m, 1H), 4.6 (s, 2H), 5.9 (tt, 1H), 6.4 (d, 1H), 6.5-6.6 (m, 3H), 6.9-7.4 (m, 7H), 7.6 (m, 1H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][S:10]([C:13]1[CH:14]=[C:15]([C:19]2[NH:23][C:22]([C:24]3[N:28]([CH2:29][C:30]([O:32][CH2:33][S:34][CH3:35])=[O:31])[N:27]=[C:26]([C:36]([F:39])([F:38])[F:37])[CH:25]=3)=[CH:21][CH:20]=2)[CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:11]>>[Br:1][C:25]1[C:26]([C:36]([F:39])([F:38])[F:37])=[N:27][N:28]([CH2:29][C:30]([O:32][CH2:33][S:34][CH3:35])=[O:31])[C:24]=1[C:22]1[NH:23][C:19]([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([S:10]([CH3:9])(=[O:12])=[O:11])[CH:14]=2)=[CH:20][CH:21]=1
Reactant: CSCOC(=O)Cn1nc(C(F)(F)F)cc1-c1ccc(-c2cccc(S(C)(=O)=O)c2)[nH]1
Reactant: O=C1CCC(=O)N1Br
Product: CSCOC(=O)Cn1nc(C(F)(F)F)c(Br)c1-c1ccc(-c2cccc(S(C)(=O)=O)c2)[nH]1

Procedure:
Following bromination with N-bromosuccinimide, the title compound 32 is prepared starting from methylthiomethyl 2-(5-(5-(3-(methylsulfonyl)phenyl)-1H-pyrrol-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetate 31.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[F:19][C:20]1[CH:21]=[CH:22][C:23]([O:29][CH3:30])=[C:24](B(O)O)[CH:25]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:22]3[CH:21]=[C:20]([F:19])[CH:25]=[CH:24][C:23]=3[O:29][CH3:30])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: COc1ccc(F)cc1B(O)O
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3cc(F)ccc3OC)cccc2c1N
Yield: 81.5 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (150 mg, 0.485 mmol) and 5-fluoro-2-methoxy-phenylboronic acid (170 mg, 1.000 mmol) were reacted to afford the title compound (140 mg, 81% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.54 (br, 1H), 7.89 (m, 1H), 7.75-7.67 (m, 2H), 7.14-7.04 (m, 2H), 6.99-6.92 (m, 1H), 3.67 (s, 3H), 3.45 (apparent quartet, J=7.0 Hz, 2H), 1.65 (apparent sextet, J=7.0 Hz, 2H), 1.00 (t, J=7.0 Hz, 3H). MS APCI, m/z=355 (M+H). HPLC 1.67 min.
Reaction SMILES: [CH2:1]([NH:7][C:8]([NH2:10])=[O:9])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[C:11]([CH2:13][C:14](O)=[O:15])#[N:12].C(OC(=O)C)(=O)C>O>[NH2:12][C:11]1[N:7]([CH2:1][C:2]2[O:6][CH:5]=[CH:4][CH:3]=2)[C:8](=[O:9])[NH:10][C:14](=[O:15])[CH:13]=1
Reactant: N#CCC(=O)O
Reactant: NC(=O)NCc1ccco1
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: Nc1cc(=O)[nH]c(=O)n1Cc1ccco1
Temperature: 25 °C
Yield: 53.1 %

Procedure:
A solution of furfurylurea (7.0 g, 50.0 mmol), cyanoacetic acid (4.7 g, 55.0 mmol), and acetic anhydride (50 ml) was heated to 95° C. for 3 hours. After cooling to ambient temperature the solution was concentrated under reduced pressure to give a crude intermediate that was stirred with water (30 ml). After concentrating, the residue was dissolved in water (100 ml) and treated with a 50% aqueous sodium hydroxide solution (10 ml) to give a pH of 13. This solution was heated at 70° C. for 30 minutes, cooled and filtered. The wet solids were stirred in boiling ethanol for 15 minutes, cooled to ambient temperature and filtered. The filtrate was evaporated under reduced pressure to give 6-amino-1-furfuryluracil (5.5 g, 53% yield) as an orange solid.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][N:6]1[CH2:11][CH2:10][C:9]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:12][CH:8]2[CH2:7]1.O1CCOCC1>O>[CH3:5][N:6]1[CH2:11][CH2:10][C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([N:1]=[N+:2]=[N-:3])[CH:8]([OH:12])[CH2:7]1
Reactant: [N-]=[N+]=[N-]
Reactant: CN1CCC2(c3ccccc3)OC2C1
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CN1CCC(N=[N+]=[N-])(c2ccccc2)C(O)C1

Procedure:
1.4 G. of sodium azide (NaN3) in 6 ml. of water was added to a solution of 3.6 g. of 1-methyl-4-phenyl-3,4-epoxypiperidine in 20 ml. of dioxane and the resulting combined solution refluxed for two hours. A further portion of 1.4 g. of NaN3 in 6 ml. of water was then added and the reaction mixture refluxed overnight. Upon cooling 3.2 g. of crystals of the dresired 1-methyl-4-phenyl-4-azido-3-hydroxypiperidine were obtained, which had a melting point of 170°-71° C.
Reaction SMILES: P(C#N)(=O)(OCC)OCC.[CH3:11][O:12][C:13]1[C:22]([O:23][CH3:24])=[C:21]2[C:16]([C:17]([C:25]([OH:27])=O)=[CH:18][CH2:19][CH2:20]2)=[CH:15][CH:14]=1.[ClH:28].Cl.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:42]=[C:43]([O:47][CH3:48])[C:44]=1[O:45][CH3:46])[CH2:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.Cl>C(OCC)C.O.CN(C)C=O.C(N(CC)CC)C>[ClH:28].[CH3:11][O:12][C:13]1[C:22]([O:23][CH3:24])=[C:21]2[C:16]([C:17]([C:25]([N:39]3[CH2:38][CH2:37][N:36]([CH2:35][C:34]4[CH:42]=[C:43]([O:47][CH3:48])[C:44]([O:45][CH3:46])=[C:32]([O:31][CH3:30])[CH:33]=4)[CH2:41][CH2:40]3)=[O:27])=[CH:18][CH2:19][CH2:20]2)=[CH:15][CH:14]=1
Reactant: COc1ccc2c(c1OC)CCC=C2C(=O)O
Reactant: COc1cc(CN2CCNCC2)cc(OC)c1OC
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(CN2CCN(C(=O)C3=CCCc4c3ccc(OC)c4OC)CC2)cc(OC)c1OC
Yield: 67.7 %

Procedure:
Diethyl phosphorocyanidate (1.2 ml) is added dropwise to a mixture of 7,8-dimethoxy-1,2-dihydro-4-naphthoic acid (0.5 g), 1-(3,4,5-trimethoxybenzyl)piperazine dihydrochloride (0.87 g), triethylamine (0.86 g) and N,N-dimethylformamide (20 ml) with stirring. After stirring for one hour at room temperature, water (100 ml) is added to the reaction mixture and the mixture is extracted with ethyl acetate (100 ml). The organic layer is washed with water, dried and concentrated under reduced pressure. The resulting oily substance is purified by silica gel column chromatography (hexane: acetone=1:1). The product thus obtained is dissolved in ethyl ether and the solution is treated with 5N ethanolic hydrogen chloride (2 ml) to give 1-(7,8-dimethoxy-1,2-dihydro-4-naphthoyl)-4-(3,4,5-trimethoxybenzyl)piperazine hydrochloride (0.75 g) as colorless powder.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[CH3:31])[C:25]([OH:27])=O.[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]1([NH2:42])[CH2:41][O:40][CH2:39]1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[F:1][C:2]1[C:7]2[C:8]([C:18]([NH:19][CH3:20])=[O:21])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([C:25](=[O:27])[NH:42][C:38]2([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][N:32]=3)[CH2:39][O:40][CH2:41]2)[CH:28]=[CH:29][C:30]=1[CH3:31]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)c(F)c12
Reactant: NC1(c2ccccn2)COC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ccccn5)COC4)ccc3C)c(F)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.045 g, 0.107 mmol, 1.0 eq) and 3-(pyridin-2-yl)oxetan-3-amine.2HCl (0.025 g, 0.112 mmol, 1.05 eq) in DMF at 0° C. was added TEA (0.15 ml, 1.08 mmol, 10 eq) and BOP reagent (0.06 g, 0.136 mmol, 1.3 eq). The reaction mixture was stirred as rt overnight. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and the filtrate concentrated. The crude product was purified by preparative HPLC. Yield: 0.015 g (25.4%).
Reaction SMILES: [C:1]([C:5]([CH3:28])([CH3:27])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:26])([CH2:22][C:23]([OH:25])=[O:24])[CH2:18][C:19]([OH:21])=[O:20])([O:3]C)=[O:2].Cl>[OH-].[Na+]>[C:1]([C:5]([CH3:28])([CH3:27])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:26])([CH2:22][C:23]([OH:25])=[O:24])[CH2:18][C:19]([OH:21])=[O:20])([OH:3])=[O:2]
Reactant: COC(=O)C(C)(C)CCCCCCCCCCCC(O)(CC(=O)O)CC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(CCCCCCCCCCCC(O)(CC(=O)O)CC(=O)O)C(=O)O

Procedure:
A 0.90 g sample of the product of Example 10 dissolved in 10 mL of 10% NaOH was heated at 50° overnight. The solution was made pH 2 with dilute HCl and extracted with ether which was dried (NH2SO4) and evaporated. The residue dissolved and CH2Cl2 was filtered, evaporated and dried at 30°/0.5 mm to give the title compound as a yellow glass, 0.90 g. A portion crystallized twice from ether pentane gave the title compound as tiny white clusters, m. 56°-58°.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][CH2:14]1.[BH4-].[Na+].Cl.[OH-].[Na+]>CO.O>[CH2:19]([N:16]1[CH2:17][CH2:18][CH:13]([NH:12][CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:14][CH2:15]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=[N+]([O-])c1ccccc1CNC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
5955 g 2-nitrobenzaldehyde was suspended in 10 L methanol under nitrogen atmosphere and 7500 g 4-amino-1-benzyl-piperadine in 5 L methanol was added over 30 min. The reaction was stirred 1 h at RT. The reaction mixture was cooled to 0° C. and a cold solution of 1044 g sodium borohydride in 6425 mL water was added at a rate to keep the temperature below 10° C. After 1 h stirring at 0° C. and 1 h at RT the reaction was cooled again to 0° C. and aqueous 4 mol/L hydrochlorid acid was added. Then the reaction mixture was stirred at RT for 30 min and cooled again to 0-10° C. Aqueous 5 mol/L sodium hydroxide solution was added until pH=14 and the reaction was extracted with tert-butyl methylether. The organic layer was washed with water and saturated sodium chloride solution and the solvent was evaporated. The residue was dissolved in toluol, filtered and concentrated again to yield 12.8 kg of the desired product.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]#[CH:12])[N:3]=1.[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Cl:8][C:6]1[CH:7]=[C:2]([NH:19][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([Cl:13])=[CH:15][CH:16]=2)[N:3]=[C:4]([S:9][CH2:10][C:11]#[CH:12])[N:5]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: C#CCSc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: C#CCSc1nc(Cl)cc(NCc2ccc(Cl)cc2)n1

Procedure:
A stirred mixture of 6.57 g. of 4,6-dichloro-2-(2-propynylthio)pyrimidine, 4.2 g. of p-chlorobenzylamine and 3.18 g. of sodium carbonate in 50 ml. of ethanol was heated under reflux for 5 hours. The reaction mixture was filtered and the filtrate was diluted with 100 ml. of water. The precipitate thus formed was collected and recrystallized from benzene (petroleum ether was added to initiate precipitation) to afford 3.3 g. of product, m.p. 85°-88°C.