Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:14][N+:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21].Cl[C:23](=O)[C:24]([O:26][CH2:27][CH3:28])=[O:25]>N1C=CC=CC=1.C(OCC)C>[CH2:27]([O:26][C:24]([C:23]1[N:21]=[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][N:15]2[N:14]=1)=[O:25])[CH3:28]
Reactant: CCOC(=O)C(=O)Cl
Reactant: Nc1cccc[n+]1N
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCOC(=O)c1nc2ccccn2n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
To a light red solution of 1,2-diaminopyridinium 2,4,6-trimethylbenzenesulfonate (10.9 g, 35.2 mmol) in pyridine (50 mL) was added ethyl 2-chloro-2-oxoacetate (9.62 g, 7.84 mL, 70.5 mmol) at RT (exotherm reaction!). The light red solution turned into a dark red solution. The mixture was heated to 100° C. and stirred overnight. The reaction mixture was evaporated and the black residue was triturated for 30 min with Na2CO3 (saturated aqueous solution, 300 mL). The reaction mixture was extracted with dichloromethane (4×250 mL) and the combined organic layer was dried over MgSO4 and concentrated in vacuo to give 6.64 g of crude product. The crude product was suspended in diethyl ether (30 mL), filtered and washed with diethyl ether. The obtained precipitate was dried in vacuo to give the product as light brown solid (6.1 g, 31.9 mmol, 90.6%).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25])[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2].[CH3:31][N:32]([CH3:37])[CH2:33][CH2:34][CH2:35]O.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.CN(C)C1C=CN=CC=1.O.CCOC(C)=O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([O:20][CH2:35][CH2:34][CH2:33][N:32]([CH3:37])[CH3:31])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25])[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2]
Reactant: CN(C)CCCO
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)OCCCN(C)C)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 15 %

Procedure:
To a solution of 4-((2S,4R)-1-acetyl-4-((isopropoxycarbonyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoic acid (for a preparation see Intermediate 21) (164 mg, 0.400 mmol) and 3-(dimethylamino)propan-1-ol (206 mg, 1.998 mmol) in DMF (3 mL) were added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (153 mg, 0.799 mmol) and N,N-dimethylpyridin-4-amine (4.88 mg, 0.040 mmol). The resulting mixture was stirred at room temperature for 2 h, the reaction mixture was diluted with water and EtOAc was added. The layers were separated and the aqueous phase was extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was dissolved in a 1:1 MeOH/DMSO mixture and was purified by MDAP (HpH). The appropriate fractions were combined and concentrated under reduced pressure to give 3-(dimethylamino)propyl 4-((2S,4R)-1-acetyl-4-((isopropoxycarbonyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoate (29.3 mg, 15%) as a viscous colourless oil. LCMS (Formate, 2 min), Rt=0.75 min, MH+=476.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:21]=[CH:20][C:11]([CH2:12][CH:13]3[S:17][C:16](=[O:18])[NH:15][C:14]3=[O:19])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:22][CH2:23][C@H:24]([OH:39])[CH2:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([OH:38])=[C:31]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH:32]=1>>[O:18]=[C:16]1[NH:15][C:14](=[O:19])[CH:13]([CH2:12][C:11]2[CH:20]=[CH:21][C:8]([N:5]3[CH2:6][CH2:7][CH:2]([NH:22][CH2:23][C@H:24]([OH:39])[CH2:25][O:26][C:27]4[CH:28]=[CH:29][C:30]([OH:38])=[C:31]([NH:33][S:34]([CH3:37])(=[O:35])=[O:36])[CH:32]=4)[CH2:3][CH2:4]3)=[CH:9][CH:10]=2)[S:17]1
Reactant: CS(=O)(=O)Nc1cc(OC[C@@H](O)CN)ccc1O
Reactant: O=C1CCN(c2ccc(CC3SC(=O)NC3=O)cc2)CC1
Product: CS(=O)(=O)Nc1cc(OC[C@@H](O)CNC2CCN(c3ccc(CC4SC(=O)NC4=O)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from 5-[4-(4-oxo-piperidin-1-yl)-benzyl]-thiazolidine-2,4-dione (which was obtained in Example 38) and N-[5-((2S)-3-amino-2-hydroxy-propoxy)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 14) according to the procedure of Example 73 as a grey solid; mp>70° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.45–1.55 (m, 2 H), 1.85–2.00 (m, 2 H), 2.60–2.90 (m, 6 H), 2.94 (s, 3 H), 3.23 (dd, J=14.0, 3.8 Hz, 1 H), 3.60–4.00 (m, 5 H), 4.49 (dd, J=8.8, 3.9 Hz, 1 H), 6.64 (dd, J=8.8, 3.0 Hz, 1 H), 6.75–6.90 (m, 4 H), 7.04 (d, J=8.6 Hz, 2 H); MS (ES) m/z: 564.8 (MH+, 100%); HRMS Calcd. for C25H33N4O7S2 (MH+): 565.1791. Found: 565.1783.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([OH:25])=[C:9]([C:11]2[CH2:15][CH2:14][CH2:13][C:12]=2[C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=2)[C:19]([OH:21])=[O:20])[CH:10]=1)(=[O:4])=[O:3].C(=O)([O-])[O-].[K+].[K+].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CC(C)=O.C(OCC)C.O>[CH2:32]([O:20][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][CH:24]=[C:16]([C:12]2[CH2:13][CH2:14][CH2:15][C:11]=2[C:9]2[CH:10]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=[CH:7][C:8]=2[O:25][CH2:11][C:9]2[CH:10]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:17]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CS(=O)(=O)c1ccc(O)c(C2=C(c3cccc(C(=O)O)c3)CCC2)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCOCC
Product: CS(=O)(=O)c1ccc(OCc2ccccc2)c(C2=C(c3cccc(C(=O)OCc4ccccc4)c3)CCC2)c1

Procedure:
A stirred mixture of 3-{2-[5-methylsulfonyl-2-(hydroxy)- -phenyl]-cyclopent-1-enyl}-benzoic acid (65 mg, 0.2 mmol), potassium carbonate (138 mg, 1 mmol) and benzyl bromide (75 mg, 0.44 mmol) in acetone (4 ml) was refluxed for 16 hours then cooled and diluted with diethyl ether/water. The organic phase was dried (MgSO4), evaporated to dryness and purified using Biotage with ethyl acetate/iso-hexane (1:19) to yield the title compound as a colourless gum. (85 mg, 84%).
Reaction SMILES: Br[C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.[OH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=1>C1(C)C=CC=CC=1>[C:2]12([C:16]3[CH:17]=[C:18]([C:2]45[CH2:11][CH:6]6[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]6)[CH2:3]4)[CH2:9]5)[C:13]([OH:12])=[CH:14][C:15]=3[OH:19])[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2
Reactant: Oc1cccc(O)c1
Reactant: BrC12CC3CC(CC(C3)C1)C2
Solvent: Cc1ccccc1
Product: Oc1cc(O)c(C23CC4CC(CC(C4)C2)C3)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 130 °C
Reaction time: 24 h
Yield: 69.8 %

Procedure:
75.0 g of 1-bromoadamantane (349 mmol), 9.58 g of 1,3-dihydroxybenzene (87.0 mmol), 25 mL of toluene and stirrer were charged in a 300 mL recovery flask and heated and agitated at 130° C. for 24 hours under nitrogen flow. A solvent was removed under reduced pressure to obtain a solid. The obtained solid was purified by column chromatography, thus obtaining 23.0 g of 4,6-di(1-adamantyl)-1,3-dihydroxybenzene (60.8 mmol; the yield was 69.9%).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[N:31]([Si](C(C)C)(C(C)C)C(C)C)[CH:30]=[CH:29]3)=[CH:22][C:21]=1[NH:45][C:46](=[O:55])[C:47]1[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=1>C1COCC1>[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[NH:31][CH:30]=[CH:29]3)=[CH:22][C:21]=1[NH:45][C:46](=[O:55])[C:47]1[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=1
Reactant: COc1ccc(C(=O)Nc2cc(-c3ccc4c(ccn4[Si](C(C)C)(C(C)C)C(C)C)c3)ccc2N)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2cc(-c3ccc4[nH]ccc4c3)ccc2N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
TBAF (26 μL) was added to a solution of 440 (14 mg, 0.027 mmol) in THF (50 μL), stirred 1 h at room temperature, diluted with ethyl, washed with water, the organic layer was dried (MgSO4), filtered and concentrated. The compound was purified by preparative TLC to afford the title compound 441 (5.4 mg, 56% yield).
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([C:16]([N:18]4[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]4)=O)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[CH:11]1[C:12]2[C:13]3([CH2:16][N:18]4[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]4)[CH2:15][CH:6]([C:5]4[C:14]3=[CH:1][CH:2]=[CH:3][CH:4]=4)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(N1CCC(O)CC1)C12CC(c3ccccc31)c1ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a cooled suspension (0° C.) of-(9,10-dihydro-9,10-methanoanthracen-9-ylcarbonyl)piperidin-4-ol (described above)(19.6 mmol) in diethyl ether (200 mL) under nitrogen was added lithium aluminum hydride (1.49 g, 39.2 mmol, 8 eq of hydride) in portions. The suspension was stirred at 0° C. for 30 min and warmed to room temperature. After 18 h at room temperature, the excess reagent was carefully quenched with the following in sequence: water (1.5 mL), 2.5N NaOH (1.5 mL) and additional water (4.5 mL). The suspension was stirred vigorously until the aluminum salts became a granular white solid. The suspension was diluted with ethyl acetate (100 mL), dried with a small amount of anhydrous magnesium sulfate and filtered. The filter cake was rinsed thoroughly with ethyl acetate. The solvent was removed to yield the title compound as a white solid in 88% yield. TLC analysis (Rf 0.54, 10% methanol in CHCl3) MS (Cl, CH4) m/z 306 (M+1,100), 334 (M+29,14), 288 (62), 114 (8).
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[N:24](COCC[Si](C)(C)C)[C:18]4[CH:19]=[N:20][NH:21][C:22](=[O:23])[C:17]=4[C:16]=3[C:33]#[C:34][Si](CC)(CC)CC)[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:3][CH2:2]1.C1(OC2C=C(C3N(COCC[Si](C)(C)C)C4C=NN(COCC[Si](C)(C)C)C(=O)C=4C=3C)C=CC=2OC(F)F)CC1>O>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[NH:24][C:18]4[CH:19]=[N:20][NH:21][C:22](=[O:23])[C:17]=4[C:16]=3[C:33]#[CH:34])[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:13])[F:14])[CH2:2][CH2:3]1
Reactant: CC[Si](C#Cc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)n(COCC[Si](C)(C)C)c2cn[nH]c(=O)c12)(CC)CC
Agent: Cc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Solvent: O
Product: C#Cc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)[nH]c2cn[nH]c(=O)c12
Yield: 52.8 %

Procedure:
Reaction was carried out in the same manner as in Example 4-(b) except for using 32 mg (0.053 mmol) of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-triethylsilylethynyl-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 16-(a) in place of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-methyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer after separation was washed successively with water and then with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. To the obtained concentrate were added methanol and water, and the mixture was subjected to ultrasonic wave treatment and the precipitated solid was collected by filtration. The obtained solid was washed successively with water and then with diethyl ether and dried under reduced pressure to obtain 10 mg of the title compound as a beige solid. (Yield: 51%)
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][N:41]=[N+]=[N-])=[CH:33][CH:32]=2)=[C:28]([CH:44]([CH3:46])[CH3:45])[NH:27][N:26]=1)(=[O:3])[CH3:2]>O1CCCC1.[C].[Pd]>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][NH2:41])=[CH:33][CH:32]=2)=[C:28]([CH:44]([CH3:46])[CH3:45])[NH:27][N:26]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCN=[N+]=[N-])cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCN)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.7 %

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-azidopropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole (1.6 g) in tetrahydrofuran (25 mL) was added 10% palladium-carbon powder (300 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure to give the title compound (1.5 g).
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].CC(C)([O-])C.[K+].[CH2:34]1[CH2:55][O:54][CH:36]([CH2:37][CH:38]2[CH:45]([O:46][CH:47]3[CH2:52][CH2:51][CH2:50][CH2:49][O:48]3)[CH2:44][CH:43]3[CH:39]2[CH2:40][CH:41](O)[O:42]3)[O:35]1>C1COCC1>[CH2:34]1[CH2:55][O:54][CH:36]([CH2:37][C@H:38]2[C@H:45]([O:46][CH:47]3[CH2:52][CH2:51][CH2:50][CH2:49][O:48]3)[CH2:44][C@H:43]([OH:42])[C@@H:39]2[CH2:40]/[CH:41]=[CH:8]\[CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3])[O:35]1
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OC1CC2C(CC(OC3CCCCO3)C2CC2OCCO2)O1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(O)CCC/C=C\C[C@@H]1[C@@H](CC2OCCO2)[C@H](OC2CCCCO2)C[C@@H]1O
Reaction time: 8 h

Procedure:
(4-Carboxybutyl)triphenylphosphonium bromide (22.03 g) and potassium t-butoxide (1-M, 99.4 ml) were treated in THF (100 ml) to give a ylide, to which was added the previously obtained lactol (58) at 0° C., and the mixture was kept at room temperature overnight. The reaction was worked up in the usual manner to give the carboxylic acid
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]3O)=[CH:12][CH:13]=2)[N:8]([CH3:29])[S:7]1(=[O:31])=[O:30].C(Cl)Cl.CCN(S(F)(F)[F:42])CC>CO.O>[F:32][C:2]1([F:1])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])[CH2:17][CH:16]3[F:42])=[CH:12][CH:13]=2)[N:8]([CH3:29])[S:7]1(=[O:31])=[O:30]
Reactant: CCN(CC)S(F)(F)F
Reactant: CN1c2nc(C3CCN(C(=O)OC(C)(C)C)CC3O)ccc2N(CC2CC2(F)F)S1(=O)=O
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CN1c2nc(C3CCN(C(=O)OC(C)(C)C)CC3F)ccc2N(CC2CC2(F)F)S1(=O)=O
Temperature: 25 °C

Procedure:
To a round bottom flask was added tert-butyl 4-{1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridin-5-yl}-3-hydroxypiperidine-1-carboxylate (27-1) (74 mg, 0.156 mmol), anhydrous DCM (1 mL), the reaction mixture was cooled to 0 C while stirring under an atmosphere of nitrogen, then added DAST (0.035 ml, 0.265 mmol) dropwise. Reaction mixture was continued to stir at 0 C for 10 minutes, then permitted to warm to room temperature. After 1 hour reaction mixture was diluted with MeOH & drops of water, then purified by reverse-phase chromatography (10-100% CH3CN:0.1% TFA in H2O) to yield tert-Butyl 4-{1-[(2,2-difluorocyclopropypmethyl]-3-methyl-2,2-dioxido-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridin-5-yl}-3-fluoropiperidine-1-carboxylate (29-1). HRMS (M+H)+: observed=477.1785, calculated=477.1778.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[NH:13][C:14](=[O:22])[C@:15]([OH:21])([CH3:20])[C:16]([F:19])([F:18])[F:17].[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][N:25]=1>N1C=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([S:9]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][N:25]=2)(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[NH:13][C:14](=[O:22])[C@:15]([OH:21])([CH3:20])[C:16]([F:19])([F:18])[F:17]
Reactant: Cc1ccc(N)nc1
Reactant: C[C@@](O)(C(=O)Nc1ccc(S(=O)(=O)Cl)c(Cl)c1Cl)C(F)(F)F
Solvent: c1ccncc1
Product: Cc1ccc(NS(=O)(=O)c2ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c2Cl)nc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 16 %

Procedure:
A mixture of (R)-N-(2,3-dichloro-4-chlorosulphonylphenyl)-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (200 mg, 0.5 mmol) (Method 1) and 2-amino-5-methylpyridine (81 mg, 0.80 mmol) in pyridine (5 ml) was stirred at 80° C. overnight. The mixture was cooled to ambient temperature, poured onto water (50 ml) and extracted with EtOAc (2×25 ml). The organic layer was separated, washed with 1 M aqueous hydrochloric acid, saturated sodium hydrogen carbonate solution, brine, dried and evaporated to give the title compound as a solid (40 mg, 0.08 mmol); NMR: 1.6 (s, 3H), 2.1 (s, 3H), 7.1 (d, 1H), 7.6 (d, 1H), 7.75 (s, 1H), 8.1 (s, 2H); m/z 470.
Reaction SMILES: [CH2:1]1[CH:8]2[NH:9][CH:3]([CH2:4][C:5]([CH2:7]2)=[O:6])[CH2:2]1.Cl.O.C(Cl)Cl.[OH-].[Na+].[C:17](OC(=O)C)(=[O:19])[CH3:18]>>[C:17]([N:9]1[CH:8]2[CH2:1][CH2:2][CH:3]1[CH2:4][C:5](=[O:6])[CH2:7]2)(=[O:19])[CH3:18]
Reactant: O=C1CC2CCC(C1)N2
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1C2CCC1CC(=O)C2
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A suspension of nortropinone hydrochloride (1 g, 6.187 mmol) in acetic anhydride was stirred at 70° C. for 3 h. Water was added, the mixture was boiled for 30 min and cooled down to room temperature. CH2Cl2 and 1N aqueous NaOH was added until pH 9 was reached. The mixture was extracted 2 times with CH2Cl2, the combined organic layers were dried over Na2SO4, filtrated and the solution was evaporated to dryness to give 0.7 g of 8-Acetyl-8-aza-bicyclo[3.2.1]octan-3-one (4a).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH:11]1([C:17]2[C:22]([C:23](OCCC#N)=[O:24])=[C:21]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[C:20]([C:37](OCC)=[O:38])=[C:19]([CH:42]([CH3:44])[CH3:43])[N:18]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[OH-].[K+]>C1(C)C=CC=CC=1>[CH:11]1([C:17]2[C:22]([CH2:23][OH:24])=[C:21]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[C:20]([CH2:37][OH:38])=[C:19]([CH:42]([CH3:44])[CH3:43])[N:18]=2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: CCOC(=O)c1c(C(C)C)nc(C2CCCCC2)c(C(=O)OCCC#N)c1-c1ccc(F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)c1nc(C2CCCCC2)c(CO)c(-c2ccc(F)cc2)c1CO
Temperature: -78 °C
Reaction time: 8 h

Procedure:
35.7 ml (53.5 mmol) of a 1.5 molar solution of diisobutylaluminum hydride in toluene are added at -78° C. under a nitrogen atmosphere to 2.5 g (5.35 mmol) of the compound from Example 54 dissolved in 50 ml of dry toluene, and the mixture is stirred for 1 hour at -78° C. and overnight at room temperature. 20% strength potassium hydroxide solution is added to the mixture with ice-cooling and it is extracted several times using toluene.
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[CH:15]([C@:18]1([C:24]([N:26]2[CH2:31][CH2:30][N:29]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=3)[CH2:28][CH2:27]2)=[O:25])[CH2:22][CH2:21][C@@H:20]([NH2:23])[CH2:19]1)([CH3:17])[CH3:16].[O:42]1[CH2:47][CH2:46][C:45](=O)[CH2:44][CH2:43]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CCOC(C)=O>[CH:15]([C@:18]1([C:24]([N:26]2[CH2:31][CH2:30][N:29]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:40])([F:41])[F:39])[CH:33]=3)[CH2:28][CH2:27]2)=[O:25])[CH2:22][CH2:21][C@@H:20]([NH:23][CH:45]2[CH2:46][CH2:47][O:42][CH2:43][CH2:44]2)[CH2:19]1)([CH3:17])[CH3:16]
Reactant: O=C1CCOCC1
Reactant: CC(C)[C@]1(C(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)CC[C@@H](N)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@]1(C(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)CC[C@@H](NC2CCOCC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1R,3S)-3-isopropyl-3-({4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}carbonyl)cyclopentanamine bis(trifluoroacetate) (98 mg, 0.16 mmol), tetrahydro-4H-pyran-4-one (0.044 mL, 0.48 mmol) and triethylamine (0.067 mL, 0.48 mmol) in methylene chloride (5 mL) was added sodium triacetoxyborohydride (68 mg, 0.32 mmol). After being stirred at room temperature overnight, the reaction mixture was diluted with EtOAc and washed with saturated Na2CO3. The aqueous layer was extracted with EtOAc three times. The combined organic layers were dried (MgSO4), concentrated and purified on silica gel eluting with EtOAc to 1% Et3N/EtOAc providing 63 mg (84%) of the desired product, which was further purified by HPLC to give the product as diTFA salt. MS calculated for C25H36F3N3O2: (M+H) 468; found 468.2.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([N:10]2[CH2:22][CH2:21][C:20]3[N:19]4[C:14]([CH2:15][CH2:16][CH2:17][CH2:18]4)=[CH:13][C:12]=3[C:11]2=[O:23])[N:5]=[CH:4][CH:3]=1.[CH3:24][N:25]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[C:27]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:52][CH2:51][N:50]([CH:53]4[CH2:56][O:55][CH2:54]4)[CH2:49][C@@H:48]3[CH3:57])=[CH:43][N:42]=2)[C:26]1=[O:58].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[CH3:24][N:25]1[C:26](=[O:58])[C:27]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:52][CH2:51][N:50]([CH:53]4[CH2:54][O:55][CH2:56]4)[CH2:49][C@@H:48]3[CH3:57])=[CH:43][N:42]=2)=[CH:28][C:29]([C:2]2[C:7]([CH:8]=[O:9])=[C:6]([N:10]3[CH2:22][CH2:21][C:20]4[N:19]5[C:14]([CH2:15][CH2:16][CH2:17][CH2:18]5)=[CH:13][C:12]=4[C:11]3=[O:23])[N:5]=[CH:4][CH:3]=2)=[CH:30]1
Reactant: O=Cc1c(Cl)ccnc1N1CCc2c(cc3n2CCCC3)C1=O
Reactant: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(B3OC(C)(C)C(C)(C)O3)cn(C)c2=O)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(N4CCc5c(cc6n5CCCC6)C4=O)c3C=O)cn(C)c2=O)nc1
Temperature: 100 °C
Yield: 49.8 %

Procedure:
A 100-mL round-bottomed flask equipped with a reflux condenser was charged with 4-chloro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrido[3,4-b]indolizin-2(1H)-yl)nicotinaldehyde 139a (100 mg, 0.30 mmol), (S)-1-methyl-3-(5-(2-methyl-4-(oxetan-3-yl)-piperazin-1-yl)pyridin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 191j (146 mg, 0.30 mmol), PdCl2(dppf) (25 mg, 0.030 mmol), K3PO4.trihydrate (160 mg, 0.60 mmol), sodium acetate (49 mg, 0.60 mmol), acetonitrile (20 mL), and water (3 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 3 h. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 1:3 petroleum/ethyl acetate to afford 149a as a yellow solid (97 mg, 50%). MS-ESI: [M+H]+ 649