Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(O[C:16](=O)[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([C:24](=[O:29])N(OC)C)[CH2:20][CH2:19]1)(C)(C)C.[O:31]1[C:36]2[CH:37]=[CH:38][C:39](C=O)=[CH:40][C:35]=2[O:34][CH2:33][CH2:32]1>>[O:31]1[C:36]2[CH:37]=[CH:38][C:39]([CH2:16][NH:17][C@H:18]3[CH2:19][CH2:20][C@H:21]([C:24]([C:9]4[S:10][C:6]5[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:7]=5[N:8]=4)=[O:29])[CH2:22][CH2:23]3)=[CH:40][C:35]=2[O:34][CH2:33][CH2:32]1
Reactant: CON(C)C(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Reactant: Cc1cccc2scnc12
Reactant: O=Cc1ccc2c(c1)OCCO2
Product: Cc1cccc2sc(C(=O)[C@H]3CC[C@H](NCc4ccc5c(c4)OCCO5)CC3)nc12

Procedure:
Using 4-methyl-benzothiazole (5 mmol), [trans-4-(methoxy-methyl-carbamoyl)-cyclohexyl]-carbamic acid tert-butyl ester (2.5 mmol) and 2,3-dihydro-benzo[1,4]dioxine-6-carbaldehyde (0.3 mmol) according to the same protocol as that described for example 1, steps 1.a to 1.c, the title compound was obtained as a colourless solid (58 mg).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1([C:21](OCC)=[O:22])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.CCOCC>C1COCC1.C(Cl)(Cl)Cl>[F:7][C:8]1([CH2:21][OH:22])[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:12][CH2:13]1
Reactant: CCOC(=O)C1(F)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(F)(CO)CC1
Temperature: 0 °C
Yield: 68.6 %

Procedure:
Lithium aluminium hydride (1M in THF) (2.36 mL, 2.361 mmol) was added dropwise to a stirred solution of 1-tert-butyl 4-ethyl 4-fluoropiperidine-1,4-dicarboxylate (325 mg, 1.180 mmol) in THF (5.90 mL) cooled to 0° C. After 10 min ether (15 mL) was added and the reaction was quenched by sequential dropwise addition of water (0.1 mL), 10% NaOH (0.1 mL) and water (0.3 mL). The mixture was stirred at room temperature and the lithium salts that had precipitated were filtered off and washed with fresh ether. The organic filtrates were combined and solvent was removed in vacuo to leave a clear gum. The crude product was taken up in chloroform and loaded onto a 25+M Biotage silica column. Chromatography, eluting with a gradient of EtOAc in hexanes, gave tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (189 mg, 0.810 mmol, 69%) as a clear gum.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].C1(C)C(S([C:32]2([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:40](=[O:41])[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33]2=[O:42])(=O)=O)=CC=CC=1>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([C:32]4([C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=5)[C:33](=[O:42])[C:34]5[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=5)[C:40]4=[O:41])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Cc1ccccc1S(=O)(=O)C1(c2ccccc2)C(=O)c2ccccc2C1=O
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)C1(c1ccccc1)N1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (2.2 g, 10 mmol), K2CO3 (1.6 g, 11.6 mmol) and 2-toluenesulfonyl-2-phenyl-1,3-indandione (4.2 g, 10 mmol) in acetonitrile (50 ml) was heated at reflux for 3 hours. The mixture was cooled and the insolubles were filtered. The solvent was removed on a rotary evaporator. The residue was purified twice using a flash chromatography column (SiO2, 45 g and 40 g; eluted with DCM). The product thus purified was recrystallized from ethanol (30 ml) and isopropyl ether, yield: 2.8 g, m.p. 149°-150° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([C:22](=[O:34])[NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[CH2:17][CH2:16]3)[N:9]=[CH:8][N:7]=1)=[O:5])C.[H-].C([Al+]CC(C)C)C(C)C>C1COCC1.CCOC(C)=O.O>[F:32][C:30]([F:31])([F:33])[C:26]1[CH:25]=[C:24]([NH:23][C:22]([N:18]2[C:19]3[C:15](=[CH:14][C:13]([O:12][C:10]4[CH:11]=[C:6]([CH:4]([OH:5])[OH:3])[N:7]=[CH:8][N:9]=4)=[CH:21][CH:20]=3)[CH2:16][CH2:17]2)=[O:34])[CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)c1cc(Oc2ccc3c(c2)CCN3C(=O)Nc2cccc(C(F)(F)F)c2)ncn1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(Nc1cccc(C(F)(F)F)c1)N1CCc2cc(Oc3cc(C(O)O)ncn3)ccc21
Temperature: 0 °C
Reaction time: 20 h

Procedure:
To solution of 100 mg (0.21 mMol) 6-[1-(3-trifluoromethyl-phenylcarbamoyl)-2,3-dihydro-1H-indol-5-yloxy]-pyrimidine-4-carboxylic acid ethyl ester (Expl. 72) in 3 ml THF at −78° C. are added 1.39 ml of a 1 M solution of diisobutylaluminium hydride in THF. After 20 h at −78° C., the mixture is slowly warmed up to 0° C. and stirred at this temperature for 2 h. Then the mixture is diluted with EtOAc and water, the aqueous layer separeted off and extracted twice with EtOAc. The organic phases are washed with water and brine, dried (Na2SO4) and after addition of 0.25 g of SiO2 concentrated. The resulting powder is put on top of a chromatography column (SiO2; EtOAc/hexane 1:4) and the title compound eluated with EtOAc/hexane 1:1: MS: [M+1]+=446; HPLC: AtRet=13.0.
Reaction SMILES: O.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH:13]=[CH:12][C:11]2=[O:15])=[CH:6][CH:5]=1.[O:16]=[C:17]([NH:32][C@@H:33]1[CH2:37][CH2:36][NH:35][CH2:34]1)[CH2:18][NH:19][C:20](=[O:31])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1.[NH4+].[OH-]>CCOC(C)=O.CO>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:11](=[O:15])[CH2:12][CH:13]([N:35]3[CH2:36][CH2:37][C@@H:33]([NH:32][C:17](=[O:16])[CH2:18][NH:19][C:20](=[O:31])[C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:30])[F:29])[CH:22]=4)[CH2:34]3)[CH2:14]2)=[CH:8][CH:9]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCNC1
Reactant: COc1ccc(N2CC=CC2=O)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(N2CC(N3CC[C@@H](NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2=O)cc1
Yield: 21.5 %

Procedure:
A slurry of water (20 μL, 0.10 mmol), 1-(4-methoxyphenyl)-1,5-dihydro-2H-pyrrol-2-one (200 mg, 1.06 mmol) and N-{2-oxo-2-[(3R)-pyrrolidin-3-ylamino]ethyl}-3-(trifluoromethyl)benzamide (666 mg, 2.12 mmol) was heated to 90° C. overnight. The crude mixture was subjected to flash chromatography (1% NH4OH, 15% MeOH, EtOAc) to afford, as a mixture of diastereomers, N-(2-{[(3R)-1′-(4-methoxyphenyl)-5′-oxo-1,3′-bipyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide as a white solid (115 mg, 21%). 1H-NMR (CDCl3) δ: 1.50-1.82 (m, 1H), 1.83-2.00 (m, 1H), 2.18-2.40 (m, 1H), 2.40-2.58 (m, 1H), 2.56-2.81 (m, 3H), 2.83-3.00 (m, 2H), 3.29-3.33 (m, 2H), 3.60-3.71 (m, 2H), 3.79 (s, 3H), 4.04-4.20 (m, 2H), 4.38-4.47 (m, 1H), 6.94 (m, 2H), 7.19-7.30 (m, 2H), 7.69-7.80 (m, 2H), 7.99 (d, J=7.8 Hz, 1H), 8.18 (s, 1H). MS m/z: 505 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH:11]1[CH2:15][CH2:14][CH:13]([CH2:16][NH:17][C:18](=[O:35])[CH2:19][S:20][C:21]2[N:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)=[CH:23][N:22]=2)[CH2:12]1.ClC(Cl)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CCOCC>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][N:11]1[CH2:15][CH2:14][CH:13]([CH2:16][NH:17][C:18](=[O:35])[CH2:19][S:20][C:21]2[N:22]=[CH:23][C:24]([C:27]3[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=3)=[CH:25][N:26]=2)[CH2:12]1
Reactant: COc1ccc(-c2cnc(SCC(=O)NCC3CCNC3)nc2)cc1
Reactant: O=Cc1cccc(Cl)c1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(Cl)Cl
Product: COc1ccc(-c2cnc(SCC(=O)NCC3CCN(Cc4cccc(Cl)c4Cl)C3)nc2)cc1
Reaction time: 8 h

Procedure:
2,3-Dichlorobenzaldehyde (115 mg, 0.66 mmol, 1.5 equiv.) was added to N-(pyrrolidin-3-(RS)-ylmethyl)-2-[5-(4-methoxyphenyl)pyrimidin-2-ylthio]acetamide in dichloroethane (3.4 mL, 0.44 mmol). Excess Na(OAc)3BH (0.2 g, 0.9 mmol, ~3 equiv.) was added and the resulting suspension was stirred vigorously overnight. The reaction mixture was diluted with ether and quenched with 1 M hydrochloric acid to afford a cloudy mixture. The organic layer was carefully removed and the aqueous phase made basic with 5 M aqueous sodium hydroxide to pH 11. After thorough extraction with ethyl acetate, the combined organic phases was washed with brine, then dried over sodium sulfate and concentrated. Chromatography on silica (0-10% methanol in ethyl acetate) afforded N-(1-(2,3-dichlorobenzyl)pyrrolidin-3-(RS)-ylmethyl)-2-[5-(4-methoxyphenyl)pyrimidin-2-ylsulfanyl]acetamide that was converted to the hydrochloride salt using 4 M hydrochloric acid solution in dioxane and ether (60 mg).
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]([NH2:17])([C:9]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:10])[CH2:5][CH:6]([CH3:8])[CH3:7].C1COCC1.[Li+].[OH-]>CO.O>[CH3:7][CH:6]([CH3:8])[CH2:5][C:4]([NH2:17])([C:9]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:10])[C:3]([OH:18])=[O:2]
Reactant: COC(=O)C(N)(CC(C)C)C(=O)c1cccnc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)CC(N)(C(=O)O)C(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 57.7 %

Procedure:
To a solution of 4-methyl-2-[pyridine-3-carbonyl]-amino-pentanoic acid methyl ester (0.80 g, 3.3 mmol), in methanol (8 mL), THF (3 mL) was added LiOH (0.7 g, 16.9 mmol), dissolved in water (9 mL). The mixture was allowed to stir at room temperature (25° C.) over 2.5 h. Methanol and THF was stripped off from the reaction mass, acidified the reaction mass using 1.5NHCl (pH=1). Extracted the reaction mass with ethyl acetate (100 mL) thrice and dried over sodium sulphate and concentrated to obtain product as pale yellow solid (0.45 g, 60%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=NN)[CH3:11])([O-:3])=[O:2].[OH-:14].[K+].[CH2:16]([N:22]1[CH2:26][C:25](=O)[CH2:24][C:23]1=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>O1CCOCC1.[O-2].[Mn+4].[O-2]>[CH2:16]([N:22]1[C:26](=[O:14])[CH:25]2[CH:24]([C:10]2([CH3:11])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[C:23]1=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CC(=NN)c1ccccc1[N+](=O)[O-]
Reactant: CCCCCCN1CC(=O)CC1=O
Reactant: [OH-]
Agent: [Mn+4]
Agent: [K+]
Agent: [O-2]
Solvent: C1COCCO1
Product: CCCCCCN1C(=O)C2C(C1=O)C2(C)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 12 %

Procedure:
To a solution of 1-(2-nitrophenyl)-1-ethanone hydrazone (Preparation 137, 4.00 g, 22.3 mmol) in dioxan (50 ml) was added manganese (IV) oxide (4.27 g, 49.2 mmol) followed by a saturated ethanolic solution of potassium hydroxide (2.0 ml), and the reaction mixture was stirred at room temperature for 4 h. The suspension was filtered through Celite™ washing with dioxan (ca. 150 ml) to give a deep red solution. 1-Hexyl-1H-pyrrole-2,4-dione (Preparation 56, 4.05 g, 22.4 mmol) was added to the solution and the reaction mixture was stirred at room temperature overnight before heating under reflux for 24 h. The reaction mixture was cooled to room temperature, filtered through Celite™ and concentrated in vacuo a crude dark brown oil. This was purified by chromatography in two batches using a Biotage Flash 40M™ cartridge packed with silica gel (90 g) eluting with dichloromethane:hexane (2:1) to afford an 8:1 exo:endo mixture of diastereomers of the title compound as a pale brown oil (880 mg, 12%).
Reaction SMILES: [I:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.Br[CH:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.II>CC#N>[CH:23]([N:6]1[CH:7]=[C:2]([I:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: O=c1[nH]cc(I)c(=O)[nH]1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: II
Solvent: CC#N
Product: O=c1[nH]c(=O)n(C(c2ccccc2)c2ccccc2)cc1I
Temperature: 84 °C
Yield: 88.4 %

Procedure:
5-Iodouracil (0.10 g, 0.42 mmol) was suspended in dry MeCN (2.1 mL) and N,O-bis(trimethylsilyl)acetamide (0.25 mL, 1.05 mmol) was added under nitrogen atmosphere. When the reaction mixture turned clear, bromodiphenyl methane (0.15 g, 0.63 mmol) and a catalytic amount of I2 were added and the reaction mixture was heated at 84° C. for 4 hrs. After cooling to room temperature, the mixture was concentrated under reduced pressure, diluted with EtOAc and washed with water. The aqueous phase was extracted with EtOAc (3×15 mL), the combined organic layers were washed with brine, dried over Na2SO4 and the solvent was removed under reduced pressure. The crude was purified by column chromatography using a Teledyne ISCO apparatus (cyclohexane:EtOAc 60:40) to afford the title compound (0.15 g, 87%) as white solid. 1H NMR (400 MHz, CDCl3): δ 7.02 (s, 1H), 7.14-7.18 (m, 4H), 7.38-7.45 (m, 6H), 7.46 (s, 1H), 8.58 (s, 1H). MS (ESI) in/Z: 405 [M-H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24]C)=O)=[CH:17][CH:16]=3)[CH:11]=[C:10]([C:26]([F:29])([F:28])[F:27])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl-].[NH4+:31].N>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([CH2:21][C:22]([NH2:31])=[O:24])=[CH:19][CH:20]=3)[CH:11]=[C:10]([C:26]([F:27])([F:28])[F:29])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: [NH4+]
Reactant: COC(=O)Cc1ccc(Cc2cc(C(F)(F)F)nc(-c3cccc(Cl)c3)n2)cc1
Agent: N
Agent: [Cl-]
Solvent: CO
Product: NC(=O)Cc1ccc(Cc2cc(C(F)(F)F)nc(-c3cccc(Cl)c3)n2)cc1
Temperature: 100 °C
Reaction time: 70 h
Yield: 67.8 %

Procedure:
A 20-mL vial was charged with methyl 2-(4-((2-(3-chlorophenyl)-6-(trifluoromethyl)pyrimidin-4-yl)methyl)phenyl)acetate (0.136 g, 0.32 mmol) and ammonium chloride (0.052 g, 0.97 mmol, 3.0 eq.) in methanol (4 mL). To this mixture was added NH3 (8.0 mL, 7N in methanol, 56.0 mmol). The vial was sealed and the resulting mixture was stirred at 100° C. for 70 h. After this time, the crude reaction was concentrated under reduced pressure and the residue absorbed on silica (2 g) then purified by chromatography on silica using hexanes/ethyl acetate (10:0 to 0:10) as eluent followed by preparative HPLC (water/acetonitrile with 0.05% TFA) to afford the title compound (0.088 g, 67%) as a white solid. MW=405.80. M.p. 170-172° C. 1H NMR (DMSO-d6, 500 MHz) δ 8.37-8.33 (m, 2H), 7.93 (s, 1H), 7.68 (ddd, J=8.0, 2.0, 1.0 Hz, 1H), 7.62 (t, J=8.0 Hz, 1H), 7.43 (br s, 1H), 7.34 (d, J=8.0 Hz, 2H), 7.23 (d, J=8.0 Hz, 2H), 6.82 (br s, 1H), 4.30 (s, 2H), 3.33 (s, 2H); APCI MS m/z 406 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([O:24][CH3:25])=[CH:8][C:9]2[O:14][C:13](=[O:15])[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:11]([CH3:22])[C:10]=2[CH:23]=1.[C:26]1([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(O)(C)C.C([O-])(=O)/C=C/C([O-])=O>CC(C)=O>[CH3:25][O:24][C:7]1[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:35]2[CH2:36][CH2:37][N:32]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:33][CH2:34]2)=[CH:23][C:10]2[C:11]([CH3:22])=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:13](=[O:15])[O:14][C:9]=2[CH:8]=1
Reactant: COc1cc2oc(=O)c(-c3ccccc3)c(C)c2cc1OCCCCl
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CC(C)O
Solvent: CC(C)=O
Product: COc1cc2oc(=O)c(-c3ccccc3)c(C)c2cc1OCCCN1CCN(c2ccccc2)CC1
Yield: 66 %

Procedure:
Method B (40 h at 50° C.); starting materials: 6-(3-chloropropoxy)-7-methoxy-4-methyl-3-phenyl-2H-1-benzopyran-2-one (example 79) and 1-phenylpiperazine; yield 66%; fusion point 168°-170° C. (from isopropanol). Fumarate: method E; yield 95%; fusion point 219°-221° C. (from acetone).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:18][CH:17]2[O:19][CH:13]([CH2:14][N:15]([CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][C:24]=3[F:31])[CH2:16]2)[CH2:12]1)(C)(C)C.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>ClCCl>[OH:37][C:35]([C:34]([F:39])([F:38])[F:33])=[O:36].[NH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:18][CH:17]2[O:19][CH:13]([CH2:14][N:15]([CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][C:24]=3[F:31])[CH2:16]2)[CH2:12]1
Reactant: CC(C)(C)OC(=O)NCCCN1CC2CN(CCOc3ccc(C#N)cc3F)CC(C1)O2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(OCCN2CC3CN(CCCN)CC(C2)O3)c(F)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(3-{7-[2-(4-Cyano-2-fluoro-phenoxy)-ethyl]-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl}-propyl)-carbamic acid isopropyl ester (5.8 g, from step (ii) above) was taken in dry dichloromethane (25 ml) and cooled to 0° C. Trifluoroacetic acid (75 ml) was added drop by drop and the reaction mixture was stirred at RT for 2 h under nitrogen atmosphere. Solvent and trifluoroacetic acid were evaporated under reduced pressure to give the TFA salt of the sub-title compound (9 g) as an oil.
Reaction SMILES: CO[C:3]1[CH:4]=[CH:5][C:6]2N=[CH:11][CH:10]=[C:9]([C@@H](O)[C@H]3N4C[C@H](C=C)[C@@H](CC4)C3)[C:7]=2[CH:8]=1.C1C=CC=CC=1.[C:31]([O:34]CC)(=[O:33])[CH3:32]>>[C@@H:32]1([C:31]([OH:34])=[O:33])[C:8]2[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][CH2:10][CH2:11]1
Reactant: CCOC(C)=O
Reactant: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccc(OC)cc12
Solvent: c1ccccc1
Product: O=C(O)[C@H]1CCCc2ccccc21

Procedure:
The quinine salt was suspended in 180 mL of ethyl acetate and the suspension was washed with 1N hydrochloric acid (2×92 mL). The mixture was then dried (NaSO4), filtered and concentrated. The residue was dissolved in hexane and crystallized to give (S)-1,2,3,4-tetrahydro-1-naphthoic acid (14.27 g 0.08 mol), m.p. 54°-56° C. α!D -62.76° (c=1.0165, benzene).
Reaction SMILES: CO[C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[C:18]([C:19]([NH2:21])=[O:20])=[CH:17][N:16]=3)[CH2:10][CH2:9]2)=[CH:5][C:4]=1[O:30][CH2:31][CH2:32]C.Cl.Cl.COC(=O)C1C(C(F)(F)F)=CC(NC2CCNCC2)=NC=1.[Cl:57]C1C=CC(C=O)=CC=1OCC>>[Cl:57][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[C:18]([C:19]([NH2:21])=[O:20])=[CH:17][N:16]=3)[CH2:10][CH2:9]2)=[CH:5][C:4]=1[O:30][CH2:31][CH3:32]
Reactant: CCCOc1cc(CN2CCC(Nc3cc(C(F)(F)F)c(C(N)=O)cn3)CC2)ccc1OC
Reactant: CCOc1cc(C=O)ccc1Cl
Agent: COC(=O)c1cnc(NC2CCNCC2)cc1C(F)(F)F
Agent: Cl
Product: CCOc1cc(CN2CCC(Nc3cc(C(F)(F)F)c(C(N)=O)cn3)CC2)ccc1Cl

Procedure:
The title compound was prepared in analogy to the synthesis of 6-[1-(4-methoxy-3-propoxy-benzyl)-piperidin-4-ylamino]-4-trifluoromethyl-nicotinamide (example 197) from 6-(piperidin-4-ylamino)-4-trifluoromethyl-nicotinic acid methyl ester dihydrochloride (intermediate B7) and 4-chloro-3-ethoxy-benzaldehyde (intermediate E2) in a yield of 13.1 mg (19%). MS (ISP): 458.3 [M+H]+.
Reaction SMILES: Br[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[C:4]2[N:9]([C:24]3[C:25]4[C@H:32]([CH3:33])[CH2:31][CH2:30][C:26]=4[N:27]=[CH:28][N:29]=3)[CH2:10][C:11]3([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[C:3]=12.[CH3:34][N:35](C=O)C>O.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:8][C:7]1[C:2]([C:34]#[N:35])=[C:3]2[C:11]3([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[CH2:10][N:9]([C:24]3[C:25]4[C@H:32]([CH3:33])[CH2:31][CH2:30][C:26]=4[N:27]=[CH:28][N:29]=3)[C:4]2=[CH:5][CH:6]=1
Reactant: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4c3ccc(Cl)c4Br)c21
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4c3ccc(Cl)c4C#N)c21
Temperature: 95 °C
Yield: 33 %

Procedure:
To a solution (R)-tert-butyl 4-bromo-5-chloro-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (0.200 g, 0.375 mmol) in DMF (2 mL) was added zinc cyanide (0.088 g, 0.75 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.022 g, 0.019 mmol). The mixture was heated at about 95° C. for 2 days. After cooling, the mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaHCO3 solution and brine, dried and concentrated. The residue was purified by flash chromatography on silica gel (EtOAc hexanes, 1:1) to give (R)-tert-butyl 5-chloro-4-cyano-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (0.060 g, 33%) as a oil. LCMS (APCI+) m/z 480, 482 [M+H]+; Rt=4.51 min.
Reaction SMILES: [Br:1][C:2]1[C:7](Br)=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[Cl-].[Li+].C([Mg]Cl)(C)C.CN([CH:20]=[O:21])C>C1COCC1>[Br:1][C:2]1[C:7]([CH2:20][OH:21])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Clc1cnc(Br)c(Br)c1
Reactant: CN(C)C=O
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cc(Cl)cnc1Br
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To a solution of 2,3-dibromo-5-chloropyridine (60 g, 221 mmol) in THF (500 mL) was added a solution of isopropylmagnesium chloride lithium chloride solution in THF (1.3M, 185 mL) at −40° C. over about 30 min. The solution was stirred for 30 min at −40° C. and DMF (50 mL) was added. The resulting solution was warmed up to room temperature and stirred for 30 min. The reaction was quenched with 1 N HCl (400 mL) and MTBE (200 mL) was added. Organic layer was separated and washed twice with 5% aqueous NaHCO3 (200 mL). The solvent was removed under vacuum at 50° C. The resulting solids (aldehyde intermediate) were dissolved in methanol (400 mL). The solution was cooled to 5° C. under an ice bath. NaBH4 (3.6 g) was added slowly over 30 min while maintaining the reaction temperature below room temperature. The reaction mixture was stirred for another 30 min followed by addition of water (125 mL). The resulting mixture was concentrated under vacuum to approximately 150 ml. Solids precipitated during the concentration. The suspension was stirred vigorously at room temperature for 1 h and solids were collected by filtration. The wet cake was dried in a vacuum oven over night at 60° C. to give 1 (45.6 g, 93%) as a solid. 1H NMR (CDCl3, 400 MHz): δ 8.26 (d, J=2.5 Hz, 1H), 7.88 (d, J=2.5 Hz, 1H), 4.73 (d, J=5.8 Hz, 2H), 2.33 (t, J=11.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz): δ 147.12, 138.48, 138.39, 136.14, 132.06, 62.76.
Reaction SMILES: [I-].[CH:2]([C:4]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][N:8]([C:16]([N:18]1[CH:22]=[CH:21][N+:20]([CH3:23])=[CH:19]1)=[O:17])[CH2:9]2)=[O:3].N1(CCN)C[CH2:28][O:27][CH2:26]C1.C(N(CC)CC)C>ClCCl>[N:20]1([CH2:21][CH2:22][NH:18][C:16]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:4]=3[CH:2]=[O:3])[CH2:9]2)=[O:17])[CH2:23][CH2:28][O:27][CH2:26][CH2:19]1
Reactant: COc1ccc2c(c1C=O)CCN(C(=O)n1cc[n+](C)c1)C2
Reactant: NCCN1CCOCC1
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1C=O)CCN(C(=O)NCCN1CCOCC1)C2
Temperature: 25 °C
Reaction time: 24 h
Yield: 58.7 %

Procedure:
A mixture of 3-(5-formyl-6-methoxy-3,4-dihydro-1H-isoquinoline-2-carbonyl)-1-methyl-3H-imidazol-1-ium iodide (321 mg, 0.75 mmol), 2-(morpholin-4-yl)-ethylamine (99.5 μL, 99.5 mg, 0.75 mmol) and triethylamine (106 μL, 76 mg, 0.75 mmol) in anhydrous dichloromethane (10 mL) was stirred at room temperature for 24 h. After dilution with dichloromethane (1.0 mL), the solution was washed with brine (2×5 mL), dried over MgSO4 and concentrated. The residue was purified by column chromatography over silica, eluting with a 9:1 mixture of chloroform and methanol. In this manner the title compound (154 mg, 0.44 mmol, 58.7%) was obtained.