Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C.[CH:44]([O:47][C:48]1[N:53]=[CH:52][C:51]([C@@H:54]([NH2:56])[CH3:55])=[CH:50][CH:49]=1)([CH3:46])[CH3:45]>CN(C=O)C>[CH:44]([O:47][C:48]1[N:53]=[CH:52][C:51]([C@@H:54]([NH:56][C:10]([C@H:8]2[CH2:9][C@@H:7]2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:12])[CH3:55])=[CH:50][CH:49]=1)([CH3:46])[CH3:45]
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccccc1
Reactant: CC(C)Oc1ccc([C@H](C)N)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc([C@H](C)NC(=O)[C@H]2C[C@@H]2c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Trans-2-phenyl-1-cyclopropanecarboxylic acid IM46 (0.590 g, 3.64 mmol) was dissolved in DMF (15.0 mL). N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (1.38 g, 3.63 mmol) was added. Triethylamine (1.10 mL, 7.89 mmol) was then added and the mixture was stirred for 15 minutes at room temperature. This mixture was added drop wise to a solution of (S)-1-(6-isopropoxy-pyridin-3-yl)-ethylamine IM24 (0.655 g, 3.63 mmol) dissolved in DMF (15.0 mL) over 2 minutes. The mixture was stirred at room temperature over night. The mixture was evaporated to dryness. The residue was transferred to a silica gel column and eluded with EtOAc/heptanes 1:1 to give Compound 1 as a solid. This solid was dissolved in EtOAc (50 mL) and to this solution was slowly added heptanes (50 mL). The mixture was concentrated to approx. 25 mL in vacuo and this solution was cooled in an ice/water bath. A white precipitate formed. The solids was collected by filtration and dried in vacuo to give the title compound as colorless crystals (0.794 g, 67%). LC-MS (m/z) 325.4 (MH+), tR=1.51 min (method A). 1H NMR (500 MHz, DMSO) δ 8.57-8.50 (m, 1H), 8.06 (br s, 1H), 7.65-7.57 (m, 1H), 7.30-7.24 (m, 2H), 7.20-7.14 (m, 1H), 7.10 (d, J=7.5 Hz, 2H), 6.69 (d, J=8.5 Hz, 1H), 5.25-5.16 (m, 1H), 4.98-4.88 (m, 1H), 2.24-2.15 (m, 1H), 1.94-1.88 (m, 1H), 1.41-1.32 (m, 4H), 1.26 (d, J=6.2 Hz, 6H), 1.20 (ddd, J=8.5, 6.1, 4.1 Hz, 1H). Diastereomeric excess >95% based on 1H NMR.
Reaction SMILES: CN1C2C(C(F)(F)F)=CC(NC3C=NC=CC=3)=CC=2C2CNCCC12.[CH3:26][N:27]1[C:35]2[C:30](=[CH:31][C:32]([NH:38]C3C=NC=CC=3C(F)(F)F)=[CH:33][C:34]=2[C:36]#[N:37])[C@@H:29]2[CH2:49][NH:50][CH2:51][CH2:52][C@H:28]12.Br[C:54]1[C:55]([O:61][CH3:62])=[N:56][CH:57]=[C:58]([CH3:60])[CH:59]=1.CC([O-])(C)C.[Na+]>>[CH3:62][O:61][C:55]1[C:54]([NH:38][C:32]2[CH:31]=[C:30]3[C:35](=[C:34]([C:36]#[N:37])[CH:33]=2)[N:27]([CH3:26])[C@H:28]2[CH2:52][CH2:51][NH:50][CH2:49][C@@H:29]32)=[CH:59][C:58]([CH3:60])=[CH:57][N:56]=1
Reactant: CN1c2c(C#N)cc(Nc3cnccc3C(F)(F)F)cc2[C@@H]2CNCC[C@@H]21
Reactant: COc1ncc(C)cc1Br
Agent: CC(C)(C)[O-]
Agent: CN1c2c(cc(Nc3cccnc3)cc2C(F)(F)F)C2CNCCC21
Agent: [Na+]
Product: COc1ncc(C)cc1Nc1cc(C#N)c2c(c1)[C@@H]1CNCC[C@@H]1N2C

Procedure:
The title compound was prepared by following the general method for (5-methyl-6-trifluoromethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indol-8-yl)-pyridin-3-yl-amine (Method B) as a tan solid (57 mg, 39%) from (4aS,9bR)-8-amino-6-cyano-3,4,4a,9b-tetrahydro-1H-pyrido[4,3-b]indole-2,5-dicarboxylic acid tert-butyl ester (Example 162, 150 mg, 0.46 mmol), 3-bromo-2-methoxy-5-methylpyridine (84 mg, 0.42 mmol) and NaOt-Bu (66 mg, 0.69 mmol): mp 76–80° C.; 1H NMR (300 MHz, CDCl3) δ 7.38 (m, 1H), 7.07 (d, J=2.2 Hz, 1H), 7.00 (d, J=1.8 Hz, 1H), 6.91 (d, J=1.8 Hz, 1H), 5.79 (br s, 1H), 3.99 (s, 3H), 3.63–3.51 (m, 1H), 3.23–3.00 (m, 4H), 2.98–2.79 (m, 2H), 2.73–2.26 (m, 2H), 2.18 (s, 3H), 1.99–1.81 (m, 2H); ESI MS m/z 350 [C20H23N5O+H]+.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])=[CH:5][CH:4]=1.[NH2:20][C:21]1[C:25]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[CH:24][NH:23][N:22]=1>>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:22]3[N:23]=[CH:24][C:25]([C:26]4[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=4)=[C:21]3[N:20]=2)=[CH:5][CH:4]=1
Reactant: Nc1n[nH]cc1-c1ccncc1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(C(F)(F)F)cc1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3ncc(-c4ccncc4)c3n2)cc1
Yield: 45.6 %

Procedure:
Reaction of 1-(4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (142 mg, 0.5 mmol), prepared from commercially available 4-trifluoromethyl-acetophenone according to general procedure A, and 3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; prepared from 4-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (93 mg, 46%). MS (ISP) 409.2 [(M+H)+]; mp 261° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[O:13])[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[CH2:21][C:22]([C:24]1[CH:25]=[CH:26][C:27]2[S:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=2[CH:34]=1)=[O:23].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]([CH:14]3[CH2:19][CH2:18][N:17]([CH2:21][C:22]([C:24]4[CH:25]=[CH:26][C:27]5[S:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=5[CH:34]=4)=[O:23])[CH2:16][CH2:15]3)=[O:13])[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: O=C1CSc2ccc(C(=O)CCl)cc2N1
Reactant: COc1cccc2sc(C(=O)C3CCNCC3)nc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2sc(C(=O)C3CCN(CC(=O)c4ccc5c(c4)NC(=O)CS5)CC3)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
A mixture of (4-methoxy-benzothiazol-2-yl)-piperidin-4-yl-methanone (83 mg, 0.3 mmol) and 6-(2-chloro-acetyl)-4H-benzo[1,4]thiazin-3-one (72.5 mg, 0.3 mmol, prepared as described in WO 02/096907) in DMF (1 ml) was treated with DIPEA (50 μl, 0.3 mmol) and the mixture was stirred at RT overnight. The mixture was poured on water and extracted with EtOAc. The organic layers were dried over MgSO4 and concentrated. Crystallisation from ether and MeOH gave 65 mg (45%) of title compound as a beige solid.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:11].[CH3:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)=[O:14].C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(P(C2C(OC3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=CC=3)=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH3:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[NH:21][C:18]1[CH:19]=[CH:20][C:15]([C:13](=[O:14])[CH3:12])=[CH:16][CH:17]=1
Reactant: CC(=O)c1ccc(N)cc1
Reactant: Cc1cccc([N+](=O)[O-])c1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2Oc2ccccc2P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(Nc2c(C)cccc2[N+](=O)[O-])cc1
Yield: 84.7 %

Procedure:
In a flask under an argon atmosphere are consecutively placed 2.16 g of 2-bromo-3-nitrotoluene, 1.69 g of 4-aminoacetophenone (1.25 equivalents), 229 mg of dipalladium trisdibenzylideneacetone (0.025 equivalents), 269 mg of DPEPhos (0.05 equivalents) and 4.07 g of cesium carbonate (1.25 equivalents). The toluene is added at room temperature. The heterogeneous reaction medium is purged with argon and refluxed for hours. After returning to room temperature, water and ethyl acetate are added. After separation of the phases, the organic phase is washed with water and then with a saturated NaCl solution, dried on sodium sulphate, filtered and then dry evaporated. The obtained red oil is purified by chromatography on silica (ethyl acetate/cyclohexane:5/95 to 10/90) in order to provide 2.29 g of the expected compound as a red oil.
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]([C:15]3[CH2:16][CH:17]4[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH:18]4[CH:29]=3)=[CH:12][CH:13]=2)[N:8]([CH3:30])[C:7]1=[O:31].FC(F)(F)C(O)=O>ClCCl>[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]([C:15]3[CH2:16][CH:17]4[CH2:21][NH:20][CH2:19][CH:18]4[CH:29]=3)=[CH:12][CH:13]=2)[N:8]([CH3:30])[C:7]1=[O:31]
Reactant: Cn1c(=O)n(CC2CC2(F)F)c2ccc(C3=CC4CN(C(=O)OC(C)(C)C)CC4C3)nc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1c(=O)n(CC2CC2(F)F)c2ccc(C3=CC4CNCC4C3)nc21
Reaction time: 18 h

Procedure:
tert-Butyl 5-{1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl}-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (14-1, 100 mg, 0.22 mmol) was added to a mixture of dichloromethane (2.0 mL) and trifluoroacetic acid (0.5 mL) at room temperature. After stirring for 18 h, the solvent was removed in vacuo. The resulting residue was then diluted with ethyl acetate (100 mL) and washed sequentially with saturated sodium bicarbonate (2×50 mL), water (1×50 mL) and brine (1×50 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo to give 1-[(2,2-Difluorocyclopropyl)methyl]-5-(1,2,3,3a,4,6a-hexahydrocyclopenta-[c]pyrrol-5-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (14-2) as a white solid. This material was carried on without further purification.
Reaction SMILES: [C:1]([C:3]1[NH:7][CH:6]=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:4]=1[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([F:22])[CH:14]=1)#[N:2].[H-].[Na+].[NH2:25]OP(=O)(C1C=CC=CC=1)C1C=CC=CC=1>CN(C=O)C>[NH2:25][N:7]1[C:3]([C:1]#[N:2])=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([F:22])[CH:14]=2)[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6]1
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1c[nH]c(C#N)c1-c1ccc([N+](=O)[O-])c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(N)c(C#N)c1-c1ccc([N+](=O)[O-])c(F)c1
Temperature: 80 °C
Yield: 71.6 %

Procedure:
To a solution of ethyl 5-cyano-4-(3-fluoro-4-nitrophenyl)-1H pyrrole-3-carboxylate (31.9 g, 105.2 mmol) in DMF (1.5 L) was slowly added NaH (34.54 g, 136.7 mmol). After the evolution of gas had ceased (aminooxy)(diphenyl)phosphine oxide (34.4 g, 147.3 mmol) was added in one portion. Upon addition of (aminooxy)(diphenyl)phosphine oxide the reaction mixture solidified. The reaction mixture was heated to 80° C. during which time the solids broke up and mixture stirred freely. The reaction was heated for 3 h, then cooled and the DMF was removed under reduced pressure. The remaining slurry was dissolved in EtOAc (500 mL) and filtered to remove a majority of the phosphinic acid. The filter cake was washed with EtOAc and the organics were concentrated in vacuo. The product was purified by crystallization from hot ACN to provide a tan solid (24.0 g, 75.31 mmol) in 71% yield. 1H-NMR (DMSO-d6) δ 8.21 (app t, J=8.4 Hz, 1H), 7.73 (s, 1H), 7.71 (dd, J=12.4, 2.0 Hz, 1H), 7.48 (m, 1H), 6.72 (s, 2H), 4.11 (q, J=7.2 Hz, 2H), 1.14 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Br-].CS([NH:6][C:7]([CH2:9][CH2:10][CH2:11][CH2:12][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:8])(=O)=O.[Na].[C:33](OCC)(=O)[CH3:34].Cl>CS(C)=O>[C:7]([NH2:6])(=[O:8])[CH2:9][CH2:10][CH2:11]/[CH:12]=[CH:33]\[CH3:34]
Reactant: CCOC(C)=O
Reactant: CS(=O)(=O)NC(=O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Br-]
Agent: [Na]
Solvent: CS(C)=O
Product: C/C=C\CCCC(N)=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 27.0 g. (52.0 mmoles) of (4-methanesulfonylaminocarbonyl-n-butyl)triphenylphosphonium bromide in 46 ml. of dimethyl sulfoxide is added dropwise 49.3 ml. (98.6 mmoles) of a 2.0M solution of sodium methylsulfonylmethide in dimethyl sulfoxide. To the resultant red solution is added over the course of 15 minutes a solution of 6.6 g. (20.8 mmoles) of the hemiacetal prepared in Example IV in 63 ml. of dimethyl sulfoxide. After being stirred for an additional 2.0 hours, the reaction is poured onto 600 ml. of ice-water. The cold aqueous layer is covered with ethyl acetate and acidified to pH~3 with 10% hydrochloric acid. The acidified aqueous layer is further extracted with ethyl acetate (2 × 200 ml.) and the combined organic extracts are washed with water followed by brine. Drying the organic layer over anhydrous sodium sulfate and concentration affords the crude product which is triturated with ether. Concentration of the ether provides N-methanesulfonyl 7-[2β-(1,3-oxathialan-2-yl)-3α -(tetrahydropyran-2-yloxy)-5α-hydroxycyclopent-1α-yl)]-cis-5-heptenamide (VI).
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:15][CH2:16][CH:17]([F:19])[F:18])[N:3]=1>[Ni].C1COCC1.CO>[NH2:12][C:11]1[C:2]([NH2:1])=[N:3][C:4]([O:15][CH2:16][CH:17]([F:19])[F:18])=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N)nc1OCC(F)F
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc(N)c(N)nc1OCC(F)F

Procedure:
Prepared analogously to example 154d by hydrogenation of the product obtained in (803a) using Raney nickel in THF and methanol.
Reaction SMILES: ClC1C=CC(CN2C(=O)C(CN3CCN(C)CC3)=CC(C3C=CC4OCCC=4C=3)=N2)=CC=1.[C:33]([C:36]1[C:37](=[O:61])[N:38]([CH2:51][CH:52]=[CH:53][C:54]2[CH:59]=[CH:58][C:57]([Cl:60])=[CH:56][CH:55]=2)[N:39]=[C:40]([C:42]2[CH:43]=[CH:44][C:45]3[O:49][CH2:48][CH2:47][C:46]=3[CH:50]=2)[CH:41]=1)(O)=[O:34]>>[Cl:60][C:57]1[CH:58]=[CH:59][C:54]([CH:53]=[CH:52][CH2:51][N:38]2[C:37](=[O:61])[C:36]([CH2:33][OH:34])=[CH:41][C:40]([C:42]3[CH:43]=[CH:44][C:45]4[O:49][CH2:48][CH2:47][C:46]=4[CH:50]=3)=[N:39]2)=[CH:55][CH:56]=1
Reactant: O=C(O)c1cc(-c2ccc3c(c2)CCO3)nn(CC=Cc2ccc(Cl)cc2)c1=O
Agent: CN1CCN(Cc2cc(-c3ccc4c(c3)CCO4)nn(Cc3ccc(Cl)cc3)c2=O)CC1
Product: O=c1c(CO)cc(-c2ccc3c(c2)CCO3)nn1CC=Cc1ccc(Cl)cc1
Yield: 31.1 %

Procedure:
The general procedure of Example 1 (4) was carried out by use of 4-carboxy-2-(4-chlorocinnamyl)-6-(2,3-dihydro-1-benzofuran-5-yl)-2H-pyridazin-3-one, to thereby yield the title compound as a pale yellow powder (yield: 31.1%).
Reaction SMILES: Cl[C:2]1[N:19]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=2)[NH2:30])[CH2:23][CH2:22]1>>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][NH:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:30][C:29]3[CH:31]=[CH:32][CH:33]=[C:27]([N:24]4[CH2:23][CH2:22][N:21]([CH3:20])[CH2:26][CH2:25]4)[CH:28]=3)[N:19]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: CN1CCN(c2cccc(N)c2)CC1
Reactant: Fc1ccccc1CNc1cccn2nc(Cl)nc12
Product: CN1CCN(c2cccc(Nc3nc4c(NCc5ccccc5F)cccn4n3)c2)CC1

Procedure:
N(8)-(2-Fluoro-benzyl)-N(2)-[3-(4-methyl-piperazin-1-yl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-fluoro-benzyl)-amine (0.3227 g, 1.166 mmol) and 3-(4-methylpiperazin-1-yl)aniline (223 mg, 1.17 mmol) in a manner analogous to Example 2d. Product isolated as a red foam (102.96 mg, 20.5%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.19 (s, 1H), 7.98 (d, J=7.3 Hz, 1H), 7.43-7.06 (m, 7H), 6.74 (t, J=14.3, 7.1 Hz, 1H), 6.46 (d, J=8.6 Hz, 1H), 6.35 (m, 2H), 4.59 (d, J=6.4 Hz, 2H), 3.11 (s, 4H), 2.45 (s, 4H), 2.22 (s, 3H). MS=432 (MH)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([CH2:12][NH:13][C:14]3[C:19]([NH2:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][N:15]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[CH2:25](OC(OCC)OCC)C>C(O)=O>[CH3:1][S:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([CH2:12][N:13]3[C:14]4=[N:15][CH:16]=[C:17]([C:21]([F:24])([F:22])[F:23])[CH:18]=[C:19]4[N:20]=[CH:25]3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CSc1nc2ccc(CNc3ncc(C(F)(F)F)cc3N)cc2s1
Reactant: CCOC(OCC)OCC
Solvent: O=CO
Product: CSc1nc2ccc(Cn3cnc4cc(C(F)(F)F)cnc43)cc2s1
Temperature: 90 °C
Reaction time: 2 h
Yield: 79.3 %

Procedure:
A mixture of N2-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-5-(trifluoromethyl)pyridine-2,3-diamine (0.89 g, 2.39 mmol), triethoxymethane (30 mL) and HCOOH (0.6 g) was stirred at 90° C. for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 2:1 to 0:1 petroleum ether/EtOAc to afford 2-(methylthio)-6-((6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazole as a light yellow solid (0.77 g, 79.3%). 1H NMR (300 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.77 (d, J=1.2 Hz, 1H), 8.57 (d, J=1.8 Hz, 1H), 8.00 (d, J=1.2 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.49-7.46 (m, 1H), 5.68 (s, 2H), 2.77 (s, 3H). LCMS (ESI) m/z 381 (M+H)+.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]1[CH:22]=[CH:21][O:20][N:19]=1)C1C=CC=CC=1>C1COCC1.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]1[CH:22]=[CH:21][O:20][N:19]=1
Reactant: O=C1N2C[C@@H](CC[C@H]2c2ccon2)N1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C1N(O)[C@@H]2CC[C@@H](c3ccon3)N1C2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94.7 %

Procedure:
A mixture of (2S,5R)-6-(benzyloxy)-2-(isoxazol-3-yl)-1,6-diazabicyclo[3.2.1]octan-7-one (196 mg, 0.656 mmol) and 10% Pd/C (80 mg) in THF (20 mL) was stirred at rt for 1.5 h under H2. The reaction mixture was then filtered and concentrated. The residue was washed with Et2O (3×) and dried under high vacuum to afford (2S,5R)-6-hydroxy-2-(isoxazol-3-yl)-1,6-diazabicyclo[3.2.1]octan-7-one (130 mg, 98%), which was in the next step directly. ESI-MS (EI+, m/z): 210 [M+H]+.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]([F:18])([F:17])[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([OH:16])([CH3:15])[C:13]#[CH:14])=[CH:8][CH:7]=1.[I:19]I.O>CO>[I:19][C:14]#[C:13][C:12]([C:9]1[CH:8]=[CH:7][C:6]([O:5][C:4]([F:17])([F:18])[F:3])=[CH:11][CH:10]=1)([OH:16])[CH3:15]
Reactant: C#CC(C)(O)c1ccc(OC(F)(F)F)cc1
Reactant: II
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(O)(C#CI)c1ccc(OC(F)(F)F)cc1
Reaction time: 3 h

Procedure:
40 ml of concentrated sodium hydroxide solution were added dropwise to a solution of 23 g (0.1 mol) of 3-(4-trifluoromethoxyphenyl)-but-1-yn-3-ol in 250 ml of methanol at 15°-20° C. in the course of 30 minutes, while stirring, and 25.4 g (0.1 mol) of iodine were simultaneously introduced in portions. After three hours, the reaction mixture was stirred into 1,000 ml of water. The initially oil reaction product crystallized on standing. The solid material was taken up in 200 ml of ethyl acetate, the solution was washed twice with 100 ml of water, and the organic phase was dried over anhydrous sodium sulphate and concentrated by evaporation under reduced pressure. The residual oil was dissolved in a small quantity of petroleum ether, the solution was cooled and the precipitated crystals were filtered off under suction. 17.2 g (=48.2% of theory) of colorless crystals of melting point 75°-76° C. were obtained.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([S:11]([CH2:14][CH3:15])(=[O:13])=[O:12])=[CH:4][N:3]=1.[NH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>>[CH2:14]([S:11]([C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[N:3][CH:4]=1)(=[O:13])=[O:12])[CH3:15]
Reactant: CCS(=O)(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: NCC1CCOCC1
Product: CCS(=O)(=O)c1cnc(NCC2CCOCC2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared according to the procedure described in Step A of Example 5 from 2-chloro-5-(ethylsulfonyl)-3-nitropyridine (Step D) and 4-aminomethyltetrahydropyran (Apollo Scientific Ltd.).
Reaction SMILES: [CH2:1]1[CH2:5]OC[CH2:2]1.[Si]([O:13][CH:14]1[CH2:23][C:22]([F:25])([F:24])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([F:26])[CH:20]=2)[C:15]1=[O:27])(C(C)(C)C)(C)C.F>N1C=CC=CC=1>[F:25][C:22]1([F:24])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([F:26])[CH:20]=2)[C:15]([CH:1]([CH3:5])[CH3:2])([OH:27])[CH:14]([OH:13])[CH2:23]1
Reactant: C1CCOC1
Reactant: CC(C)(C)[Si](C)(C)OC1CC(F)(F)c2cc(F)ccc2C1=O
Agent: F
Solvent: c1ccncc1
Product: CC(C)C1(O)c2ccc(F)cc2C(F)(F)CC1O
Temperature: 25 °C
Yield: 69 %

Procedure:
A THF solution (8 mL) of 2-((tert-butyldimethylsilyl)oxy)-4,4,6-trifluoro-3,4-dihydronaphthalen-1(2H)-one 54 (0.585 g, 1.77 mmol) was cooled to 0° C. and a solution of hydrogen fluoride in pyridine (70%, 200 μL) was added dropwise. The reaction was allowed to warm to ambient temperature over 12 h at which point the reaction was quenched with an aqueous solution of saturated sodium bicarbonate, volatiles were removed and the mixture was re-dissolved in ethyl acetate. The aqueous phase was extracted with ethyl acetate (3×), dried over sodium sulfate, filtered and concentrated to give an orange oil. The desired product, 4,4,6-trifluoro-2-hydroxy-3,4-dihydronaphthalen-1(2H)-one, was purified with a gradient heptanes/ethyl acetate eluent system on silica gel by a ISCO companion system to give the desired product as a colorless oil (0.263 g, 1.22 mmol, 69% yield). 1H NMR (400 MHz, CDCl3) δ: 8.14 (dd, J=8, 4 Hz, 1H), 7.48 (dt, J=8, 4 Hz, 1H), 7.36 (m, 1H), 4.67 (ddd, J=12, 8, 4 Hz, 1H), 3.66 (s, 1H), 3.17 (m, 1H), 2.54 (m, 1H).
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:13][CH2:12][C@@H:11]([C:14]([OH:16])=[O:15])[CH2:10]1)=O)(C)(C)C.C(=O)(O)[O-].[Na+].I[CH2:23][CH3:24].[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28]>CN(C)C=O.C(OCC)(=O)C.C(Cl)Cl>[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].[NH2:8][C@H:9]1[CH2:13][CH2:12][C@@H:11]([C:14]([O:16][CH2:23][CH3:24])=[O:15])[CH2:10]1
Reactant: CCI
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1CC[C@H](N)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.1 %

Procedure:
To a solution of (1R,3S)-3-[(tert-butoxycarbonyl)amino]cyclopentanecarboxylic acid (from Acros, 0.46 g, 2.0 mmol) in N,N-dimethylformamide (4.6 mL) was added sodium bicarbonate (0.34 g, 4.0 mmol) and iodoethane (0.64 mL, 8.0 mmol). The resulting mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate then washed with sat. sodium bicarbonate, water (2×) and brine. The organic was dried (Na2SO4), filtered, and concentrated to give the crude ester. To the crude ester was added methylene chloride (3.0 mL) and trifluoroacetic acid (1.0 mL, 13 mmol). The resulting solution was stirred for 1 h, then concentrated and dried in vacuo to give 0.25 g (46%) of the title compound. LCMS calculated for C8H16NO2 (M+H)+: m/z=158.1. Found: 158.1.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([S:7]([CH3:10])(=[O:9])=[O:8])=[CH:5][CH:6]=1.S(=O)(=O)(O)O.[N+:16]([O-])([O-:18])=[O:17].[Na+]>>[Br:1][C:2]1[S:3][C:4]([S:7]([CH3:10])(=[O:9])=[O:8])=[CH:5][C:6]=1[N+:16]([O-:18])=[O:17]
Reactant: CS(=O)(=O)c1ccc(Br)s1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CS(=O)(=O)c1cc([N+](=O)[O-])c(Br)s1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 47 %

Procedure:
2-bromo-5-methylsulfonyl-thiophene (0.3 g, 1.24 mmol) was added to the concentrated sulfuric acid at 0° C. cooling in an ice bath. The resulted mixture was stirred at 0° C. for 5 minutes. Then sodium nitrate was introduced and the mixture was stirred at 0° C. for 1 hour. After this time, the reaction mixture was poured onto to the ice-water (10 mL) and was extracted with ethyl acetate. The organic phase was dried (Na2SO4) and concentrated under vacuum. The residue was purified by silica gel chromatography using a mixture of 95:5 hexane and ethyl acetate as eluent to afford the title product as a solid (0.17 g, 47% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.37 (1H, s), 2.50 (3H, m).