Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][OH:11])[CH:6]=[C:5]([O:12][CH3:13])[C:4]=1B(O)O.[CH2:17]([O:19][C:20](=[O:41])[C@H:21]([CH2:33][C:34]1[CH:39]=[CH:38][C:37](Br)=[CH:36][CH:35]=1)[NH:22][C:23](=[O:32])[C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:31])[CH3:18]>>[CH2:17]([O:19][C:20](=[O:41])[C@H:21]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:4]2[C:3]([O:2][CH3:1])=[CH:8][C:7]([CH2:9][CH2:10][OH:11])=[CH:6][C:5]=2[O:12][CH3:13])=[CH:36][CH:35]=1)[NH:22][C:23](=[O:32])[C:24]1[C:25]([Cl:31])=[CH:26][CH:27]=[CH:28][C:29]=1[Cl:30])[CH3:18]
Reactant: CCOC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1c(Cl)cccc1Cl
Reactant: COc1cc(CCO)cc(OC)c1B(O)O
Product: CCOC(=O)[C@H](Cc1ccc(-c2c(OC)cc(CCO)cc2OC)cc1)NC(=O)c1c(Cl)cccc1Cl

Procedure:
2,6-Dimethoxy-4-(2-hydroxyethyl)benzeneboronic acid was coupled with N-(2,6-dichlorobenzoyl)-4-bromo-L-phenylalanine ethyl ester according to the procedure described in Example 8-3) to yield 1.3 g of N-(2,6-dichlorobenzoyl)-4-[2,6-dimethoxy-4-(2-hydroxyethyl)phenyl]-L-phenylalanine ethyl ester. ESMS: m/z 546 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]=1[C:17]([C:19]1[C:24]([CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:18].[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[Si:27]([O:26][CH2:25][C:24]1[C:19]([C:17]([C:3]2[N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:5]3[C:10]([C:2]=2[NH:1][C:34](=[O:37])[CH2:35][CH3:36])=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=3)=[O:18])=[N:20][CH:21]=[CH:22][CH:23]=1)([C:30]([CH3:32])([CH3:31])[CH3:33])([CH3:29])[CH3:28]
Reactant: CCOC(=O)n1c(C(=O)c2ncccc2CO[Si](C)(C)C(C)(C)C)c(N)c2ccc(Cl)cc21
Reactant: CCC(=O)Cl
Product: CCOC(=O)n1c(C(=O)c2ncccc2CO[Si](C)(C)C(C)(C)C)c(NC(=O)CC)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 2 employing 3-amino-2-[3-(tert-butyldimethylsilyloxymethyl)pyridine-2-carbonyl]-6-chloro-1-(ethoxycarbonyl)indole (step 3) and propionyl chloride. 1H-NMR (CDCl3) δ: 9.48 (1 H, br s), 8.45 (1 H, dd, J=1.5, 4.5 Hz), 8.25 (1 H, dd, J=1.5, 8.1 Hz), 8.16 (1 H, d, J=1.8 Hz), 8.08 (1 H, d, J=8.9 Hz), 7.44 (1 H, dd, J=4.6, 7.9 Hz), 7.25 (1 H, dd, J=1.8, 8.8 Hz), 5.20 (2 H, s), 3.86 (2 H, q, J=7.1 Hz), 2.50 (2 H, q, J=7.6 Hz), 1.26 (3 H, t, J=7.6 Hz), 1.00 (9 H, s), 1.00 (3 H, t, J=7.0 Hz), 0.18 (6 H, s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26](S(C)=O)[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37][NH2:38]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH:38][CH2:37][C:36]5[CH:39]=[CH:40][CH:41]=[C:34]([Cl:33])[CH:35]=5)[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)c1nccc(-c2n[nH]c3nc(NC4CCN(C(=O)OC(C)(C)C)CC4)ncc23)n1
Reactant: NCc1cccc(Cl)c1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncc3c(-c4ccnc(NCc5cccc(Cl)c5)n4)n[nH]c3n2)CC1
Temperature: 130 °C
Reaction time: 2 h

Procedure:
The mixture of 4-[3-(2-methanesulfinyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (from Example 13 supra) (230 mg, 0.50 mmol) and 3-chlorobenzylamine (283 mg, 2.0 mmol) was heated at 130° C. with stirring for 2 hours. The resulting oil was purified by chromatography (silica gel, 7 g, 200-300 mesh, eluting with dichloromethane:methanol, 50:1 to 30:1) to afford 4-{3-[2-(3-chloro-benzylamino)-pyrimidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino}-piperidine-1-carboxylic acid tert-butyl ester. (Yield 80 mg, 30.0%).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=O)=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:14])=[CH:7][CH:8]=2)[N:3]=1.[CH3:15][C:16]([S@:19]([NH2:21])=[O:20])([CH3:18])[CH3:17]>C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Cl:1][C:2]1[C:11](/[CH:12]=[N:21]/[S@@:19]([C:16]([CH3:18])([CH3:17])[CH3:15])=[O:20])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:14])=[CH:7][CH:8]=2)[N:3]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=Cc1cc2ccc(F)cc2nc1Cl
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: C1CCOC1
Product: CC(C)(C)[S@@](=O)/N=C/c1cc2ccc(F)cc2nc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.7 %

Procedure:
To a solution of 2-chloro-7-fluoroquinoline-3-carboxaldehyde (6.3 g, 30 mmol) in dry THF (200 mL) under nitrogen was added titanium isopropoxide (17.0 g, 60 mmol) and the reaction mixture stirred at r.t. for 10 minutes. (R)-2-Methyl-2-propanesulfin-amide (3.6 g, 30 mmol) was added to the reaction mixture which was stirred at r.t. for 72 h and partitioned between water (20 mL) and DCM (150 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo to give the title compound (7.2 g, 76%) as a pale yellow solid. δH (CDCl3) 9.09 (1H, s), 8.83 (1H, s), 7.96 (1H, dd, J=6.0 Hz), 7.69 (1H, d, J=7.2 Hz), 7.42 (1H, t, J=8.4 Hz), 1.32 (9H, s).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([NH2:14])=O)[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[CH2:15][S:16][CH2:17][C:3]1=2.S(Cl)(Cl)=O>CN(C)C=O>[O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]#[N:14])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[CH2:15][S:16][CH2:17][C:3]1=2
Reactant: NC(=O)c1ccc2nc3c(c(=O)n2c1)CSC3
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: N#Cc1ccc2nc3c(c(=O)n2c1)CSC3
Temperature: 70 °C

Procedure:
A mixture of 3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxamide (2.9 g., 0.012 mol) and thionyl chloride (1.5 ml) in dimethylformamide (30 ml) is heated at 70° C. for 4 hours. The reaction mixture is cooled in an ice bath. The product, which precipitates, is filtered off and washed with water. Recrystallization from methanol gives a crystalline product (1.6 g.), mp 256°-257° C.
Reaction SMILES: [CH3:1][CH:2]([C:8]([O:10]CC)=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][C:15]=1[O:21][CH3:22]>N1C=CC=CC=1>[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:8](=[O:10])[CH:2]([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:16][C:15]=1[O:21][CH3:22]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: COc1cc(N)ccc1Cl
Solvent: c1ccncc1
Product: CCOC(=O)C(C)C(=O)Nc1ccc(Cl)c(OC)c1

Procedure:
Prepared according to Procedure A using diethyl 2-methylmalonate (4.91 mL, 28.6 mmol), pyridine (3.1 mL) and 4-chloro-3-methoxyaniline (3.00 g, 19.04 mmol). The reaction mixture was heated for 5 days. The residue was purified by column chromatography on silica gel (0-30% EtOAc/hexanes) to give ethyl 3-(4-chloro-3-methoxyphenylamino)-2-methyl-3-oxopropanoate. Mass Spectrum (ESI) m/e=286.1 (M+1).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3([C:26](O)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.Cl.[NH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>CN(C=O)C>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]3([C:26]([NH:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:19][CH:20]=2)=[CH:11][CH:10]=1
Reactant: C[C@@H]1CCCN1CCc1ccc(-c2ccc(C3(C(=O)O)CCCC3)cc2)cc1
Reactant: COC(=O)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)CNC(=O)C1(c2ccc(-c3ccc(CCN4CCC[C@H]4C)cc3)cc2)CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (R)-1-(4′-(2-(2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)cyclopentanecarboxylic acid (15 mg, 0.040 mmol), methyl 2-aminoacetate hydrochloride (5.49 mg, 0.044 mmol), HATU (16.62 mg, 0.044 mmol), and TEA (0.017 mL, 0.119 mmol) in DMF (0.4 mL) was stirred at room temperature overnight. The mixture was acidified with 1M HCl and purified by HPLC to give the title compound. LCMS m/z=449.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=1.[NH2:10][NH2:11]>>[NH:10]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=1)[NH2:11]
Reactant: COc1cccc(Cl)n1
Reactant: NN
Product: COc1cccc(NN)n1
Temperature: 23 °C
Yield: 57 %

Procedure:
A mixture of 2-chloro-6-methoxypyridine (compound 12; 2.87 g, 20 mmol) and anhydrous hydrazine (11 mL, excess) was heated under argon on a steam bath overnight. The mixture was allowed to cool to 23° C. and then was extracted with Et2O (10×10 mL). The combined ether extracts were rotary evaporated to afford 1.58 g (57%) of 2-hydrazino-6-methoxypyridine 13 as a yellow liquid that was -95% pure by NMR: 1H NMR (CDCl3) δ 7.38 (pseudo-t, 1), 6.20 (d, J=8.0 Hz, 1), 6.09 (d, J=8.0 Hz, 1), 5.71 (bs, 1, exchanges upon addition of D2O, NH), 3.84 (s, 3, OCH3), 3.1 (bs, 2, exchanges upon addition of D2O, NH2). A solution of this hydrazine (1.58 g, 11 mmol) in 10 mL of absolute ethanol was combined with a solution of 1 (1.8 g, 10 mmol) in 20 mL of absolute ethanol, and the reaction mixture produced a precipitate within several minutes. The mixture was allowed to stand at 23° C. overnight. The solid was collected by suction filtration, washed with a small amount of ethanol, and was dried in vacuo, giving 1.65 g of the methoxy precursor 14. An additional 510 mg of this precipitated from the filtrate after it had been concentrated on a rotary evaporator to a small volume. Combined yield: 2.15 g (76%): mp 161-162° C. (ethanol). 1H NMR ((CD3)2SO) δ 10.45 (s, 1, exchanges upon addition of D10, OH), 8.25 (s, 1, H4), 8.04 (d, J=8.2 Hz, 1), 7.88 (pseudo-t, 1), 7.54 (d, J=8.2 Hz, 1), 7.36 (s, 1), 7.26 (d, J=8.25 Hz, 1), 6.68 (d, J=7.9 Hz, 1), 6.64 (pseudo-t, 1), 3.92 (s, 3, OCH3), 3.90 (s, 3, OCH3). Low-resolution DCI mass spectrum, m/z 284 (100%, MH+). Exposure of this compound to molten C5H5N○HCl for 10 min effected removal of the hydroxy pyridine protecting group only, by 1H NMR. Exposure to BBr3 in CH2Cl2 solution at 23° C. overnight effected the removal of the phenolic protecting group only, giving 15: mp 198-199° C. (ethanol). 1H NMR ((CD3)2SO) δ 8.17 (s, 1, H4), 7.98 (d, 1), 7.88 (pseudo-t, 1), 7.54 (d, 1), 7.12 (m, 3), 6.67 (d, 1), 3.92 (s, 3, OCH3). Low-resolution DCI mass spectrum, m/z 270 (100%, MH+). X-ray quality crystals of 15 were grown from absolute ethanol and a crystal structure determination was made; the crystal structure of the compound is shown in FIG. 1.
Reaction SMILES: [CH:1]1([C@H:7]([NH:9][C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([CH2:17]O)=[N:13][CH:12]=2)[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:40]>C(Cl)Cl>[Br:40][CH2:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]([NH:9][C@@H:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH3:8])=[O:19])=[CH:12][N:13]=1
Reactant: BrC(Br)(Br)Br
Reactant: C[C@@H](NC(=O)c1ccc(CO)nc1)C1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[C@@H](NC(=O)c1ccc(CBr)nc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
A solution of (R)-N-(1-cyclohexylethyl)-6-(hydroxymethyl)nicotinamide (3.2a, 262 mg, 1 mmol) and Ph3P (472 mg, 1.8 mmol) in CH2Cl2 (10 mL) was cooled to 0° C. and a solution of CBr4 (463 mg, 1.4 mmol) in CH2Cl2 (2 mL) was added dropwise. The reaction was allowed to warm to rt and was stirred overnight. The reaction was concentrated under reduced pressure and the residue purified by column chromatography (silica gel) using 0-40% EtOAc/hexanes to afford 3.3a (156 mg): 1H-NMR (400 MHz, CDCl3) δ 8.91 (s, 1H), 8.11 (dd, J1=8.0 Hz, J2=2.0 Hz, 1H), 7.53 (d, J=8.0 Hz, 1H), 5.98 (d, J=8.0 Hz, 1H), 4.59 (s, 2H), 4.15-4.07 (m, 1H), 1.84-1.68 (m, 5H), 1.49-1.43 (m, 1H), 1.29-1.03 (m, 8H); LC-MS (220 nm), >98%, 325.2 and 327.2 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH2:27][OH:28]>CC(C)=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:25][CH2:26][CH2:27][OH:28])[CH2:14][CH2:13]3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1nc(C2CCNCC2)c2ccc(F)cc21
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1nc(C2CCN(CCCO)CC2)c2ccc(F)cc21
Yield: 36 %

Procedure:
A mixture of 4-(6-fluoro-1-methyl-1H-indazol-3-yl)piperidine (5.0 g; 0.02 mol), potassium carbonate (8.28 g; 0.06 mol), 3-bromopropanol (2.98 g; 0.02 mol) and acetone (100 ml) was stirred and refluxed for 20 h. The reaction mixture was filtered, concentrated in vacuo and purified by chromatography on silica gel 60 with ethyl acetate:methanol (8:2, v/v) as eluent. Concentration of the appropriate fractions afforded 2.1 g (34%) of 4-(6-fluoro-1-methyl-1H-indazol-3-yl)-1-(3-hydroxypropyl)piperidine.
Reaction SMILES: [O:1]=[C:2]1[NH:6][N:5]=[C:4]([C:7]2[O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[O:3]1.[C:16](OC(=O)C)(=[O:18])[CH3:17].O>C(O)(=O)C>[O:1]=[C:2]1[N:6]([C:16](=[O:18])[CH3:17])[N:5]=[C:4]([C:7]2[O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[O:3]1
Reactant: CC(=O)OC(C)=O
Reactant: O=c1[nH]nc(-c2nc3ccccc3o2)o1
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)n1nc(-c2nc3ccccc3o2)oc1=O

Procedure:
5.0 g of 2-(2-oxo-3H-1,3,4-oxadiazole-5-yl)benzoxazole in 50 ml of acetic acid containing 5 ml of acetic anhydride was heated for 1 hour at 100°. The mixture was poured into water and the crystalline product filtered. Recrystallization from acetonitrile gave mp. of 231°-232°.
Reaction SMILES: [C:1]([C:5]12[CH2:12][O:11][C:8]([CH2:13][CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])([O:9][CH2:10]1)[O:7][CH2:6]2)([CH3:4])([CH3:3])[CH3:2].CC(C)(C)CCC12OCC(CCC)(CO1)C(C#N)O2.CC(C)(C)CCC(O)=O>>[C:1]([C:5]12[CH2:6][O:7][C:8]([C:13]#[C:14][C:15]([CH3:18])([CH3:17])[CH3:16])([O:9][CH2:10]1)[O:11][CH2:12]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)CCC12OCC(C(C)(C)C)(CO1)CO2
Agent: CC(C)(C)CCC(=O)O
Agent: CCCC12COC(CCC(C)(C)C)(OC1)OC2C#N
Product: CC(C)(C)C#CC12OCC(C(C)(C)C)(CO1)CO2

Procedure:
Using analogous methodology 4-t-butyl-1-(3,3-dimethylbutyl) -2,6,7-trioxabicyclo[2.2.2 ]octane and 1-(3,3 - dimethylbutyl) -4-n-propyl-2,6,7-trioxabicyclo[2.2.2]octane-3-carbonitrile were prepared from 4,4-dimethylpentanoic acid (G. M. Whitesides et al J. Amer. Chem. Soc. 1967, 89, 1135).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[NH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:23][CH3:24])=[C:16]([O:21][CH3:22])[CH:17]=2)[CH2:12]1>C1COCC1>[CH3:22][O:21][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:23][CH3:24])[CH2:12][N:11]([CH2:10][CH2:9][CH2:8][NH:7][C:4](=[O:5])[CH2:3][C:2]([CH3:1])=[O:6])[CH2:20][CH2:19]2
Reactant: COc1cc2c(cc1OC)CN(CCCN)CC2
Reactant: C=C1CC(=O)O1
Solvent: C1CCOC1
Product: COc1cc2c(cc1OC)CN(CCCNC(=O)CC(C)=O)CC2
Reaction time: 1.5 h
Yield: 99.8 %

Procedure:
Diketene (1.41 mL, 18.3 mmol, 1.50 equiv) was added at 0° C. to a stirred solution of 2-(3-aminopropyl)-1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline (3.05 g, 12.2 mmol, 1.00 equiv) in anhydrous THF (30 mL) under argon, and stirring was continued at room temperature for 1.5 hours. The mixture was concentrated and the residual oil washed with hexane (2×100 mL) to give 4.07 g (100%) of brown oil, which was characterized spectroscopically and used for the next reaction without purification.
Reaction SMILES: [N:1]1([C:11]([O:13]C2C=CC([N+]([O-])=O)=CC=2)=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:23]1[C:28]2([C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29]2)[CH2:27][CH2:26][NH:25][CH2:24]1.Cl.C(N(CC)CC)C.O>ClCCl>[N:1]1([C:11]([N:25]2[CH2:26][CH2:27][C:28]3([C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[CH:29]3)[CH2:23][CH2:24]2)=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: C1=CC2(CCNCC2)c2ccccc21
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCCc2ccccc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(N1CCC2(C=Cc3ccccc32)CC1)N1CCCc2ccccc21
Temperature: 150 °C
Yield: 85.1 %

Procedure:
0.4 g of 4-nitrophenyl 3,4-dihydroquinoline-1(2H)-carboxylate, 0.357 g of 4-spiroindene-piperidine hydrochloride, 0.28 ml of triethylamine and 2 ml of water are introduced into a 10 ml glass tube. The tube is sealed and then heated at 150° C. under microwave irradiation for 50 minutes. Dichloromethane is added. The organic phase is dried over magnesium sulfate and the solvent is evaporated under reduced pressure. The residue is chromatographed on silica gel with a heptane/ethyl acetate gradient from 9/1 to 0/1. 0.393 g of 1′-(3,4-dihydroquinolin-1(2H)-ylcarbonyl)spiro[indene-1,4′-piperidine] is obtained.
Reaction SMILES: [O:1]=[C:2]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)[CH:3]([CH:13]1[CH2:18][N:17](C(OC(C)(C)C)=O)[CH:16]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:15][CH2:14]1)[O:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].C(Cl)Cl.C(O)(C(F)(F)F)=O>>[C:5]([O:4][CH:3]([CH:13]1[CH2:14][CH2:15][CH:16]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[NH:17][CH2:18]1)[C:2](=[O:1])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)(=[O:6])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CC(C(OC(=O)c2ccccc2)C(=O)c2ccccn2)CCC1c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(OC(C(=O)c1ccccn1)C1CCC(c2ccccc2)NC1)c1ccccc1

Procedure:
tert-Butyl 5-{2-oxo-1-[(phenylcarbonyl)oxy]-2-(pyridin-2-yl)ethyl}-2-phenylpiperidine-1-carboxylate (29 mg, 0.058 mmol) was stirred in 4:1 DCM/TFA (5 ml) at room temperature for 3 h. Then the volatiles were removed under vacuum, and the resulting residue was purified by reverse phase HPLC (0.05% TFA-water-acetonitrile) to give the title compound. LC-MS m/e 401.19 [M+1]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23]O)=[CH:19][CH:18]=2)[C:11](=[O:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:27]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][Br:27])=[CH:19][CH:18]=2)[C:11](=[O:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrP(Br)Br
Reactant: O=c1cc(OCc2ccccc2)ccn1CCc1ccc(CO)cc1
Solvent: ClCCl
Product: O=c1cc(OCc2ccccc2)ccn1CCc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 3.00 g (8.95 mmol) 4-benzyloxy-1-[2-(4-hydroxymethyl-phenyl)-ethyl]-1H-pyridin-2-one (preparation 2a) in 30 mL of DCM is added 1.26 mL (13.4 mmol) phosphorus tribromide at 0° C. The cooling bath is removed, the mixture is stirred 2 h at RT and is diluted with half saturated aqueous NaHCO3-solution. The layers are separated and the aqueous layer is washed three times with DCM. The combined organic phase is dried over MgSO4, filtered and the solvent is evaporated to afford the product.
Reaction SMILES: [CH3:1][N:2]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[C:3](=[O:14])[CH2:4][NH:5][C@H:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C.C1([C@@H](N)C)C=CC=CC=1.C(N)C1C=CC=CC=1>>[CH3:1][N:2]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[C:3](=[O:14])[CH2:4][NH:5][CH2:6][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@H](NCC(=O)N(C)CCc1ccccn1)c1ccccc1
Agent: C[C@H](N)c1ccccc1
Solvent: NCc1ccccc1
Product: CN(CCc1ccccn1)C(=O)CNCc1ccccc1

Procedure:
The procedure of section (e) can be used generally to prepare many of the amines of formula A-H. For example, by following the latter procedure but replacing (S)-1-phenylethylamine with an equivalent amount of benzylamine, N-methyl-2-[(phenylmethyl)amino]-N-[2-(2 -pyridinyl)ethyl]acetamide was obtained via the corresponding Boc derivative. The Boc derivative had the following NMR: 1H NMR(CDCl3) δ 8.60 (d, J=5 Hz, 1H), 8.40 (m, 1H), 7.70-7.00 (m,7H), 4.55-4.52 and 4.48 (2s,2H), 3.90 (d, J=11 Hz, 1H), 3.80-3.55 (m,2H), 3.10-2.90 (m,3H), 2.90 (s,3H), 1.50 (3s,9H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]([C:12]3[CH:40]=[CH:39][C:15]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([CH2:29][CH2:30][CH2:31][C:32]([F:38])([F:37])[C:33]([F:36])([F:35])[F:34])(C(O)=O)[C:23]([OH:25])=[O:24])=[CH:14][CH:13]=3)=[O:11])=[C:8]([C:41]3[CH:46]=[CH:45][C:44]([OH:47])=[CH:43][CH:42]=3)[S:7][C:6]=2[CH:48]=1>CS(C)=O.O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]([C:12]3[CH:40]=[CH:39][C:15]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]([CH2:29][CH2:30][CH2:31][C:32]([F:38])([F:37])[C:33]([F:34])([F:35])[F:36])[C:23]([OH:25])=[O:24])=[CH:14][CH:13]=3)=[O:11])=[C:8]([C:41]3[CH:42]=[CH:43][C:44]([OH:47])=[CH:45][CH:46]=3)[S:7][C:6]=2[CH:48]=1
Reactant: O=C(c1ccc(OCCCCCC(CCCC(F)(F)C(F)(F)F)(C(=O)O)C(=O)O)cc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Solvent: O
Solvent: CS(C)=O
Product: O=C(c1ccc(OCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)O)cc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Temperature: 120 °C
Reaction time: 3 h
Yield: 71.2 %

Procedure:
2-[5-[4-[(6-Hydroxy-2-(4-hydroxyphenyl)benzo[b]-thiophen-3-yl)carbonyl]-phenoxy]pentyl]-2-(4,4,5,5,5-pentafluoropentyl)malonic acid (1.1 g, 1.58 mmol) was dissolved in dimethyl sulfoxide (10 ml) and stirred for 3 hours at 120° C. The reaction mixture was cooled to room temperature, diluted with water, and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/1) to give 2-[5-[4-[(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)carbonyl]phenoxy]-pentyl]-6,6,7,7,7-pentafluoroheptanoic acid (732 mg, Yield 71%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([O:13][CH2:14][CH3:15])[C:11]=1I)[CH:7]=[O:8])[CH3:2].C(OC1C=C(C=C(OCC)C=1I)C=O)C1C=CC=CC=1.[F:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:7]=[O:8])[CH:9]=[C:10]([O:13][CH2:14][CH3:15])[C:11]=1[C:40]1[CH:41]=[CH:42][C:37]([F:36])=[CH:38][CH:39]=1)[CH3:2]
Reactant: CCOc1cc(C=O)cc(OCC)c1I
Reactant: OB(O)c1ccc(F)cc1
Agent: CCOc1cc(C=O)cc(OCc2ccccc2)c1I
Product: CCOc1cc(C=O)cc(OCC)c1-c1ccc(F)cc1

Procedure:
The necessary intermediate 2,6-Diethoxy-4′-fluoro-biphenyl-4-carbaldehyde was prepared as described in example 94, but reacting in the Suzuki coupling 3,5-diethoxy-4-iodo-benzaldehyde (CAS NO. 338454-05-0) instead of 3-benzyloxy-5-ethoxy-4-iodo-benzaldehyde with 4-fluorophenyl boronic acid, as light yellow solid.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.[Cl:15][C:16]1[CH:17]=[C:18]([CH2:30][NH2:31])[CH:19]=[N:20][C:21]=1[O:22][CH2:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:31]([CH2:30][C:18]3[CH:19]=[N:20][C:21]([O:22][CH2:23][C:24]([F:28])([F:29])[CH:25]([F:27])[F:26])=[C:16]([Cl:15])[CH:17]=3)[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Reactant: NCc1cnc(OCC(F)(F)C(F)F)c(Cl)c1
Product: O=C1c2ccnc(Cl)c2CN1Cc1cnc(OCC(F)(F)C(F)F)c(Cl)c1
Yield: 81 %

Procedure:
The title compound is prepared in 81% yield (1.01 g, white solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (917 mg, 3.29 mmol, Step-1 of Intermediate-1) and (5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methanamine (800 mg, 2.93 mmol, Amine-87) in a similar manner to Intermediate-2.