Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[C:3]1([C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][C:18]=2[OH:19])[CH:15]([C:20]([OH:22])=[O:21])[CH2:14][CH2:13]3)=[O:9])[S:7][CH:6]=[CH:5][CH:4]=1.[CH3:23]O>>[CH3:23][O:21][C:20]([CH:15]1[C:16]2[C:12](=[CH:11][C:10]([C:8](=[O:9])[C:3]3[S:7][CH:6]=[CH:5][CH:4]=3)=[C:18]([OH:19])[CH:17]=2)[CH2:13][CH2:14]1)=[O:22]
Reactant: O=C(c1cccs1)c1cc2c(cc1O)C(C(=O)O)CC2
Reactant: CO
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)C1CCc2cc(C(=O)c3cccs3)c(O)cc21

Procedure:
Analogously to the description in Example 2, 4.0 g of 5-thenoyl-6-hydroxy-indane-1-carboxylic acid methyl ester and 20 ml of 2 N sodium hydroxide solution in 50 ml of methanol give 5-thenoyl-6-hydroxy-indane-1-carboxylic acid of melting point 183°-184° C. (from ethyl acetate/petroleum ether).
Reaction SMILES: [F:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:15]#[N:16])[C:9]=2[C:11]([F:14])([F:13])[F:12])[NH:4][C:3]=1[CH3:17].Cl[CH2:19][C:20]1[N:24]=[C:23]([C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=2)[O:22][N:21]=1>>[F:31][C:29]1[CH:30]=[C:25]([C:23]2[O:22][N:21]=[C:20]([CH2:19][N:4]3[C:5]4[C:10](=[C:9]([C:11]([F:13])([F:12])[F:14])[C:8]([C:15]#[N:16])=[CH:7][CH:6]=4)[C:2]([F:1])=[C:3]3[CH3:17])[N:24]=2)[CH:26]=[C:27]([F:32])[CH:28]=1
Reactant: Cc1[nH]c2ccc(C#N)c(C(F)(F)F)c2c1F
Reactant: Fc1cc(F)cc(-c2nc(CCl)no2)c1
Product: Cc1c(F)c2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(F)cc(F)c2)n1

Procedure:
Synthesized as described in Example 23 from 3-fluoro-2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and 3-(chloromethyl)-5-(3,5-difluorophenyl)-1,2,4-oxadiazole: MS (ES) m/z 437 (M+1).
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[C@@H:16]([NH2:18])[CH3:17].Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][N:25]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[N:29]1[C:21]([NH:18][CH:16]([C:8]2[N:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[CH3:19])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH3:17])=[C:22]2[C:26]([NH:25][CH:24]=[N:23]2)=[N:27][CH:28]=1
Reactant: Cc1ccccc1-n1c([C@H](C)N)nc2cccnc21
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1-n1c(C(C)Nc2ncnc3[nH]cnc23)nc2cccnc21
Temperature: 90 °C
Yield: 31.9 %

Procedure:
A mixture of (S)-1-(3-o-tolyl-3H-imidazo[4,5-b]pyridin-2-yl)ethylamine (330 mg, 1.31 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (430 mg, 1.83 mmol) and DIPEA (0.41 mL, 2.35 mmol) in n-butanol (2 mL) was heated at 90° C. in a sealed vial for 16 h. After cooling to RT, the crude reaction mixture was loaded onto an Isolute® SCX-2 cartridge and washed with MeOH followed by 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) to afford 168 as a white solid (155 mg, 32%). LCMS (Method K): RT 2.70 and 2.83 min [M+H]+ 371.1. 1H NMR (DMSO-d6, 400 MHz): δ 12.89 (1H, s), 8.30-7.86 (4H, m), 7.69-7.08 (5H, m), 5.47 (1H, s), 1.96 (3H, s), 1.68 (1.5H, d, J=6.77 Hz), 1.50 (1.5H, d, J=6.84 Hz). Signals split due to presence of rotamers/tautomers.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C@H:4]([OH:11])[CH2:5][C:6]([CH3:10])([CH3:9])[C:7]=1[CH3:8].[H-].[Na+].Br[CH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1.O>COCCOC>[CH:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]=[CH:25][C:16]=1[CH2:15][O:11][C@@H:4]1[CH2:5][C:6]([CH3:10])([CH3:9])[C:7]([CH3:8])=[C:2]([CH3:1])[CH2:3]1
Reactant: CC1=C(C)C(C)(C)C[C@@H](O)C1
Reactant: BrCc1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC1=C(C)C(C)(C)C[C@@H](OCc2ccc3ccccc3c2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.7 %

Procedure:
2 g (13 mmol) of (1S)-3,4,5,5-tetramethyl-3-cyclohexen-1-ol prepared in Examples 2A and 2B were dissolved in 10 ml of DME and added dropwise to a suspension of 965 mg (38.9 mmol) of NaH in 10 ml of DME at RT. After evolution of gas had ceased, 14 mmol of 2-bromomethylnaphthalene were added dropwise. Reaction was complete after stirring at RT for 12 h. 50 ml of water were added to the mixture, which was then extracted twice with 50 ml of ether. Chromatography of the residue as in Example 3A resulted in 3.7 g (97%) of the abovementioned product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31](=[O:35])[CH2:32][C:33]#[N:34])[CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])=[CH:13][CH:12]=3)[C:3]=12.[CH:36]1([CH:39]=O)[CH2:38][CH2:37]1.N1CCCCC1>CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31]([C:32](=[CH:39][CH:36]4[CH2:38][CH2:37]4)[C:33]#[N:34])=[O:35])[CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])=[CH:13][CH:12]=3)[C:3]=12
Reactant: N#CCC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4F)cc3)c3c(N)ncnc32)C1
Reactant: O=CC1CC1
Solvent: C1CCNCC1
Solvent: CO
Product: N#CC(=CC1CC1)C(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4F)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22 %

Procedure:
Into a 10 mL round-bottom flask, was placed a solution of 3-[(3R)-3-[4-amino-3-[4-(2-fluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]-3-oxopropanenitrile (60 mg, 0.13 mmol, 1.00 equiv) in methanol (10 mL), cyclopropane-carbaldehyde (50 mg, 0.71 mmol, 5.61 equiv), and piperidine (70 mg, 0.82 mmol, 6.46 equiv). The resulting solution was stirred for 30 min at room temperature and then concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (100:1) to give 0.015 g (23%) of the title compound as an off-white solid. LC-MS0: (ES, m/z): 524 [M+H]+. H-NMR (CD3OD, ppm) 8.270 (1H, s), 7.711 (2H, d), 7.316˜7.242 (4H, m), 7.149 (2H, d), 6.450 (1H, d), 4.872 (1H, s), 4.192 (1H, s), 3.966 (2H, d), 3.556˜3.488 (1H, m), 2.392˜2.363 (1H, m), 2.253˜2.209 (2H, m), 1.951 (1H, s); 1.306-1.181 (3H, m); 0.918-0.793 (2H, m)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][C@H:19]2[CH2:22][C@H:21]([C:23]([OH:25])=[O:24])[CH2:20]2)=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[NH:8][C:7]12[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.FC1C=CC(OCC2CC(C(O)=O)C2)=C2C=1NC(=O)NC12CCCCC1.C(C1C=CC(O[C@H]2C[C@H](C(O)=O)C2)=C2C=1NC(=O)NC12CCCCC1)#N.FC1C=CC(OCC2(C(O)=O)CCC2)=C2C=1NC(=O)NC12CCCCC1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][C@@H:19]2[CH2:20][C@H:21]([C:23]([OH:25])=[O:24])[CH2:22]2)=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[NH:8][C:7]12[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C1Nc2c(Cl)ccc(O[C@H]3C[C@H](C(=O)O)C3)c2C2(CCCCC2)N1
Agent: N#Cc1ccc(O[C@H]2C[C@H](C(=O)O)C2)c2c1NC(=O)NC21CCCCC1
Agent: O=C1Nc2c(F)ccc(OCC3(C(=O)O)CCC3)c2C2(CCCCC2)N1
Agent: O=C1Nc2c(F)ccc(OCC3CC(C(=O)O)C3)c2C2(CCCCC2)N1
Product: O=C1Nc2c(Cl)ccc(O[C@H]3C[C@@H](C(=O)O)C3)c2C2(CCCCC2)N1

Procedure:
trans-3-[(8′-Chloro-2′-oxo-2′,3′-dihydro-1′H-spiro[cyclohexane-1,4′-quina-zolin]-5′-yl)oxy]cyclobutanecarboxylic acid; 3-[(8′-fluoro-2′-oxo-2′,3′-dihydro-1′H-spiro[cyclohexane-1,4′-quinazolin]-5′-yl)oxymethyl]cyclobutanecarboxylic acid; trans-3-[(8′-cyano-2′-oxo-2′,3′-dihydro-1′H-spiro[cyclohexane-1,4′-quinaz-olin]-5′-yl)oxy]cyclobutanecarboxylic acid; 1-[(8′-fluoro-2′-oxo-2′,3′-dihydro-1′H-spiro[cyclohexane-1,4′-quinazolin]-5′-yl)oxymethyl]cyclobutanecarboxylic acid; trans-3-[(8′-chloro-2′-oxo-2′,3′-dihydro-1′H-spiro[cycloheptyl-1,4′-quina-zolin]-5′-yl)oxy]cyclobutanecarboxylic acid; and trans-3-[(8′-chloro-2′-oxo-2′,3′-dihydro-1′H-spiro[cyclopentyl-1,4′-quinazolin]-5′-yl)oxy]cyclobutanecarboxylic acid; or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([N+:16]([O-:18])=[O:17])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Br>CC(O)=O>[N+:16]([C:5]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:3]([OH:2])[CH:4]=1)([O-:18])=[O:17]
Reactant: COc1cc([N+](=O)[O-])ccc1Oc1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(Oc2ccccc2)c(O)c1
Temperature: 110 °C

Procedure:
3-methoxy-4-phenoxynitrobenzene(2 g, 8.15 mmol) was treated with 48% HBr (20 ml) and HOAc (20 ml), The reaction mixture was heated to 110 ° C. for 24 hours and then the reaction mixture was poured into ice and extracted with EtOAc, the organic layer was washed with brine, dried over Na2SO4. Removal of the solvent provided a brownish residue 5-Nitro-2-phenoxy-phenol which was taken to next step without further purification. (almost quantitative yield). 1H NMR (CDCl3): δ 7.91 (d,1H, 2.7 Hz), 7.72 (dd, 1H, J1=8.8 Hz, J2=2.4 Hz), 7.43 (t, 2H, J=7.9 Hz), 7.28 (d, 1H, 7.9 Hz), 7.10 (d, 1H, J=8.3 Hz), 6.78 (d, 2H, J=8.9 Hz).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1.[CH3:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[OH:23])[CH:18]=O>>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:4]=[CH:5][C:6]([C:9](=[O:11])[CH:10]=[CH:18][C:17]2[CH:20]=[CH:21][C:22]([OH:23])=[C:15]([CH3:14])[CH:16]=2)=[CH:7][CH:8]=1
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Reactant: Cc1cc(C=O)ccc1O
Product: Cc1cc(C=CC(=O)c2ccc(C(F)(F)F)cc2)ccc1O

Procedure:
This compound was synthesized from 4′-trifluoromethylacetophenone and 3-methyl-4-hydroxybenzaldehyde according to general method 1 described earlier.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][NH:9][C@H:10]([CH:13]([CH3:15])[CH3:14])[CH2:11][OH:12])[CH:5]=[CH:4][CH:3]=1.[Si:16]([C:23]1[S:24][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:27]=1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[Si:16]([C:23]1[S:24][C:25]([C:2]2[N:7]=[C:6]([CH2:8][NH:9][C@H:10]([CH:13]([CH3:15])[CH3:14])[CH2:11][OH:12])[CH:5]=[CH:4][CH:3]=2)=[CH:26][CH:27]=1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC1(C)OB(c2ccc([Si](C)(C)C(C)(C)C)s2)OC1(C)C
Reactant: CC(C)[C@H](CO)NCc1cccc(Br)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(C)[C@H](CO)NCc1cccc(-c2ccc([Si](C)(C)C(C)(C)C)s2)n1
Temperature: 80 °C
Yield: 47.6 %

Procedure:
To a solution of Example 227A (0.521 g, 1.91 mmol) in dioxane (10 mL) at ambient temperature was added 2-(t-butyldimethylsilyl)thiophene-5-boronic acid pinacol ester (0.619 g, 1.91 mmol), 2 molar cesium carbonate (0.9 mL, 1.9 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.031 g, 0.038 mmol). The solution was degassed (3× vacuum/purge N2) and heated to 80° C. overnight. The mixture was cooled and partioned between water and CH2Cl2. The organic phase concentrated and the residue triturated with ether to provide 355 mg (41%) of the title compound. MS (DCI30 ) m/z 391 (M+H); 1H NMR (300 MHz, CDCl3) δ 7.69-7.60 (m, 2H), 7.54 (d, J=7.6 Hz, 1H), 7.25 (d, J=3.6 Hz, 1H), 7.12 (d, J=7.4 Hz, 1H), 3.99 (s, 2H), 3.70 (dd, J=10.9, 4.0 Hz, 1H), 3.50 (dd, J=10.9, 6.4 Hz, 1H), 2.51 (td, J=6.5, 4.0 Hz, 1H), 1.92 (td, J=13.6, 6.8 Hz, 1H), 1.06 (d, J=6.8 Hz, 3H), 1.00-0.92 (m, 12H), 0.37-0.28 (m, 6H).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].[OH:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([N:28]([CH2:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][NH:32]2)[CH3:29])[CH2:24][CH2:23]1>C(#N)C>[OH:21][C@H:22]1[CH2:23][CH2:24][C@H:25]([N:28]([CH2:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][N:32]2[CH2:2][C:3]([N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[NH:8][C:7]3[CH:17]=[CH:18][CH:19]=[N:20][C:6]2=3)=[O:4])[CH3:29])[CH2:26][CH2:27]1
Reactant: CN(CC1CCCCN1)[C@H]1CC[C@H](O)CC1
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Solvent: CC#N
Product: CN(CC1CCCCN1CC(=O)N1c2ccccc2C(=O)Nc2cccnc21)[C@H]1CC[C@H](O)CC1

Procedure:
The title compound is prepared analogously to Example 2 from 11-(chloroacetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and trans-2-[[(4-hydroxycyclohexyl)(methyl)-amino]methyl]piperidine to give colorless crystals, mp. 183°-184.5° C. (acetonitrile).
Reaction SMILES: [CH:1](=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4].[N+:7](/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([O-:9])=[O:8].CC(O)C.CCCCCC>C(Cl)(Cl)Cl>[CH:3]([C@@H:2]([C@H:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:10][N+:7]([O-:9])=[O:8])[CH:1]=[O:6])([CH3:5])[CH3:4]
Reactant: CC(C)CC=O
Reactant: O=[N+]([O-])/C=C/c1ccccc1
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: CC(C)[C@H](C=O)[C@@H](C[N+](=O)[O-])c1ccccc1

Procedure:
The title compound was prepared from isovaleraldehyde and (E)-(2-nitrovinyl)benzene according to the general procedure. The enantiomeric excess was determined by HPLC with an AD-H column at 210 nm (2-propanol:hexane=1:99), 1.0 mL/min; major enantiomer tmajor=21.8 min, minor enantiomer tminor=17.9 min, the diastereomeric ratio was determined by 1H NMR. [α]D20=−6.5 (c=2.3, CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[NH:14][N:13]=[C:12]([CH3:15])[C:11]=2[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[H-].[Na+].I[CH:27]([CH3:29])[CH3:28].O>CN(C)C=O>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH:27]([CH3:29])[CH3:28])[N:13]=[C:12]([CH3:15])[C:11]=2[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: Cc1n[nH]c(Sc2cc(Cl)cc(Cl)c2)c1C(=O)c1ccccc1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nn(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)c1C(=O)c1ccccc1
Reaction time: 0.03 h

Procedure:
A solution containing 75 mg of [5-(3,5-dichlorophenylthio)-3-methyl-1H-pyrazol-4-yl]-phenyl-methanone in 2 ml of dry N,N-dimethylformamide (DMF) at rt under nitrogen was treated with 12 mg of sodium hydride. The mixture was then stirred for 2 min. To the mixture was added 25 μl of 2-iodopropane. The mixture was then stirred for 20 min. To the mixture was added 2 ml of water and then the mixture was extracted with ethyl acetate three times. Combined extracts were washed with brine then dried over anhydrous magnesium sulphate, filtered and evaporated. The residue 7; was purified by flash chromatography on silica gel using diethyl ether hexane (1:7) for the elution to give 32 mg of [5-(3,5-dichlorophenylthio)-1-isopropyl-3-methyl-1H-pyrazol-4-yl]-phenyl-methanone as a colourless oil. Mass spectrum (ES) m/z 405[M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]2[NH:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:26])[CH3:25])=[CH:19][CH:18]=1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([O:43][CH3:44])[C:29]=1[OH:45].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:27].[Cl:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[C:5]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:26])[CH3:25])=[CH:19][CH:18]=4)[C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][N:8]=3)[N:3]=2)[CH:31]=[C:30]([O:43][CH3:44])[C:29]=1[OH:45]
Reactant: CN(C)Cc1ccc(Nc2c(S(C)(=O)=O)cnc3ccc(Cl)nc23)cc1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: COc1cc(-c2ccc3ncc(S(C)(=O)=O)c(Nc4ccc(CN(C)C)cc4)c3n2)cc(Cl)c1O
Yield: 71.5 %

Procedure:
Following general procedure II, 6-chloro-N-{4-[(dimethylamino)methyl]phenyl}-3-(methylsulfonyl)-1,5-naphthyridin-4-amine (50 mg, 0.14 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (60 mg, 0.21 mmol) followed by formation of the dihydrochloride salt to afford the desired product (44 mg, 54%) as an orange solid: 1H NMR (500 MHz, CD3OD) δ 9.11 (s, 1H), 8.50 (d, J=9.0 Hz, 1H), 8.36 (d, J=9.0 Hz, 1H), 7.62-7.50 (m, 4H), 7.34 (d, J=2.1 Hz, 1H), 6.68 (d, J=2.0 Hz, 1H), 4.40 (s, 2H), 3.92 (s, 3H), 3.47 (s, 3H), 2.83 (s, 6H); ESI MS m/z 513 [M+H]+; HPLC>99% (AUC), tR=10.56 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([NH2:9])=[O:8])[O:5][CH:6]=1.[O:10]=[CH:11][C:12]([Cl:15])([Cl:14])[Cl:13]>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([NH:9][CH:11]([OH:10])[C:12]([Cl:15])([Cl:14])[Cl:13])=[O:8])[O:5][CH:6]=1
Reactant: NC(=O)c1cc(Br)co1
Reactant: O=CC(Cl)(Cl)Cl
Solvent: Cc1ccccc1C
Product: O=C(NC(O)C(Cl)(Cl)Cl)c1cc(Br)co1
Temperature: 95 °C

Procedure:
A mixture of 4-bromofuran-2-carboxamide 124 (0.85 g, 4.47 mmol) and chloral (0.78 mL) in xylene was heated at 95° C. for 1.5 hours. The mixture was concentrated to give 4-bromo-N-(2,2,2-trichloro-1-hydroxyethyl)furan-2-carboxamide 125 as a tan solid that was used without further purification.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][C:20]([C:23]3(O)[C:36]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:30]([C:38]4[CH:43]=[CH:42][C:41]([C:44]5[C:57]6[C:58]7=[C:59]8[C:54](=[CH:55][CH:56]=6)[CH:53]=[CH:52][CH:51]=[C:50]8[CH:49]=[CH:48][C:47]7=[CH:46][CH:45]=5)=[CH:40][CH:39]=4)(O)[C:29]4[C:24]3=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:19][CH:18]=2)[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.I.[PH2](O)=O>C(O)(=O)C>[C:44]1([C:41]2[CH:42]=[CH:43][C:38]([C:30]3[C:29]4[C:24]([C:23]([C:20]5[CH:19]=[CH:18][C:17]([C:1]6[C:14]7[C:15]8=[C:16]9[C:11](=[CH:12][CH:13]=7)[CH:10]=[CH:9][CH:8]=[C:7]9[CH:6]=[CH:5][C:4]8=[CH:3][CH:2]=6)=[CH:22][CH:21]=5)=[C:36]5[C:31]=3[CH:32]=[CH:33][CH:34]=[CH:35]5)=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:39][CH:40]=2)[C:57]2[C:58]3=[C:59]4[C:54](=[CH:55][CH:56]=2)[CH:53]=[CH:52][CH:51]=[C:50]4[CH:49]=[CH:48][C:47]3=[CH:46][CH:45]=1
Reactant: OC1(c2ccc(-c3ccc4ccc5cccc6ccc3c4c56)cc2)c2ccccc2C(O)(c2ccc(-c3ccc4ccc5cccc6ccc3c4c56)cc2)c2ccccc21
Agent: I
Agent: O=[PH2]O
Solvent: CC(=O)O
Product: c1cc2ccc3ccc(-c4ccc(-c5c6ccccc6c(-c6ccc(-c7ccc8ccc9cccc%10ccc7c8c9%10)cc6)c6ccccc56)cc4)c4ccc(c1)c2c34
Temperature: 100 °C
Reaction time: 7 h
Yield: 90.4 %

Procedure:
9,10-bis(4-(1-Pyrenyl)phenyl)-9,10-dihydroxy-9,10-dihydroanthracene (4.5 g, 5.9 mmole) was suspended in acetic acid (80 ml). To the resultant suspension, a 57% hydroiodic acid (15 ml, 0.11 mole, 20 eq) was added and the obtained mixture was stirred at 100° C. for 7 hours. To the reaction mixture, a 50% aqueous solution of hypophosphorous acid (30 ml) was added. The formed solid was separated by filtration and washed with water, methanol and acetone and a white solid (3.9 g, 90%) was obtained.
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]([CH2:10][CH2:11][CH2:12][N:13]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:14][CH2:15][CH2:16][N:17]([CH2:22][CH2:23][C:24]#[N:25])[CH2:18][CH2:19][C:20]#[N:21])[CH2:6][CH2:7][C:8]#[N:9])#[N:2].[H][H]>O1CCOCC1>[NH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH2:16][CH2:15][CH2:14][N:13]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:12][CH2:11][CH2:10][N:5]([CH2:6][CH2:7][CH2:8][NH2:9])[CH2:4][CH2:3][CH2:1][NH2:2])[CH2:22][CH2:23][CH2:24][NH2:25]
Reactant: [H][H]
Reactant: N#CCCN(CCC#N)CCCN(CCCN(CCC#N)CCC#N)Cc1ccccc1
Solvent: C1COCCO1
Product: NCCCN(CCCN)CCCN(CCCN(CCCN)CCCN)Cc1ccccc1
Yield: 91.4 %

Procedure:
6.50 g of N,N-bis(3-(N,N-bis(2-cyanoethyl)amino)propyl)benzylamine, 0.65 g of Raney Co and 100 mL of 1,4-dioxane were charged in an autoclave and a hydrogenation reaction was carried out at an initial hydrogen pressure of 9.0 MPa at 180° C. for 2 hours. After the catalyst was removed by filtration, the obtained filtrate was concentrated to dryness to give 6.16 g of the title compound as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])=[CH:4][CH:3]=1.[F:23][C:24]([F:31])([F:30])[CH2:25][S:26](Cl)(=[O:28])=[O:27]>N1C=CC=CC=1>[CH:18]1([CH2:17][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][S:26]([CH2:25][C:24]([F:31])([F:30])[F:23])(=[O:28])=[O:27])=[CH:7][CH:6]=2)[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: Nc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Solvent: c1ccncc1
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(NS(=O)(=O)CC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 42.5 %

Procedure:
A solution of 2-(4-amino-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (prepared in Example 3, 158 mg, 0.5 mmol) in pyridine (5 mL) at 25° C. was treated with 2,2,2-trifluoroethanesulfonyl chloride (63.5 μL, 0.57 mmol). The reaction was stirred at 25° C. for 48 h and was then concentrated in vacuo. High pressure liquid chromatography (Chromegasphere SI-60, 10 μM, 60 Å, 25 cm×23 cm ID, 40/60 heptane/ethyl acetate) afforded the 3-cyclopentyl-N-thiazol-2-yl-2-[4-(2,2,2-trifluoro-ethanesulfonylamino)-phenyl]-propionamide (98.1 mg, 42.4%) as a light yellow oil: EI-HRMS m/e calcd for C19H22F3N3O3S2 (M+) 461.1054, found 461.1064.
Reaction SMILES: Cl[CH2:2][Cl:3].C(Cl)(=O)C(Cl)=O.[C:10]([C:13]1[CH:21]=[CH:20][C:16](C(O)=O)=[C:15]([CH3:22])[CH:14]=1)(=[O:12])[CH3:11]>CN(C)C=O>[C:10]([C:13]1[CH:21]=[CH:20][C:16]([CH2:2][Cl:3])=[C:15]([CH3:22])[CH:14]=1)(=[O:12])[CH3:11]
Reactant: ClCCl
Reactant: CC(=O)c1ccc(C(=O)O)c(C)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(CCl)c(C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
28 ml of dichloromethane, 4 ml of oxalyl chloride, and a drop of N,N-dimethylformamide were added to 5.0 g of 4-acetyl-2-methylbenzoic acid, and the mixture was stirred for 3 hours at room temperature. After removing the solvent by distilling under reduced pressure, 5.6 g of crude 4-acetyl-2-methylbenzyl chloride was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][OH:24])=[CH:16][CH:15]=2)[C@@H:10]([O:25][CH2:26][C:27]2[CH:36]=[C:35]3[C:30]([CH:31]=[CH:32][CH:33]=[N:34]3)=[CH:29][CH:28]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:37][S:38](Cl)(=[O:40])=[O:39]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][S:38]([CH3:37])(=[O:40])=[O:39])=[CH:16][CH:15]=2)[C@@H:10]([O:25][CH2:26][C:27]2[CH:36]=[C:35]3[C:30]([CH:31]=[CH:32][CH:33]=[N:34]3)=[CH:29][CH:28]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(OCCCO)cc2)[C@@H](OCc2ccc3cccnc3c2)C1
Reactant: CS(=O)(=O)Cl
Product: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(OCCCOS(C)(=O)=O)cc2)[C@@H](OCc2ccc3cccnc3c2)C1

Procedure:
In analogy to the procedure described in example 8(b), the (3R,4R)-4-[4-(3-hydroxy -propoxy)-phenyl]-3-(quinolin-7-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester was reacted with methanesulfonyl chloride to yield the (3R,4R)-4-[4-(3-methanesulfonyloxy-propoxy)-phenyl]-3-(quinolin-7-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester as a colorless solid; MS: 571 (M+H)+.