Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:6])[CH:2]([OH:5])[CH:3]=[O:4].[OH:7][CH2:8][C:9](=[O:12])[CH2:10][OH:11]>>[OH:4][CH2:3][C:2]([C@@H:1]([C@H:8]([C@H:9]([CH2:10][OH:11])[OH:12])[OH:7])[OH:6])=[O:5]
Reactant: O=C(CO)CO
Reactant: O=CC(O)CO
Product: O=C(CO)[C@H](O)[C@@H](O)[C@@H](O)CO

Procedure:
Recently, L-fructose was prepared by aldol condensation. See S. Morgenlie, Carbohydr. Res., 107 (1982) 137-141. DL-Glyceraldehyde condensed with 1,3-dihydroxy-2-propanone catalyzed by Dowex 1 (OH-) resin to give a hexulose mixture. Crystallization of the mixture from methanol yielded 54% of DL-fructose. Treatment of the DL-fructose mixture with baker's yeast gave a product from which 62% of 2,3:4,5-di-O-isopropylidene-β-L-fructopyranose was isolated after acetonation. When L-glyceraldehyde was used as starting material, 2,3:4,5-di-O-isopropylidene-β-L-fructopyranose was isolated in 60-65% yield after acetonation of the hexulose mixture.
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([CH3:15])=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[NH2:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[OH:33])[C:28]#[N:29].C1N2CCN(CC2)C1>CN1C(=O)CCC1>[C:28]([C:27]1[CH:30]=[CH:31][C:32]2[O:33][C:2]([CH2:3][C:4]3[C:12]([O:13][CH3:14])=[CH:11][C:10]([CH3:15])=[C:9]4[C:5]=3[CH:6]=[CH:7][N:8]4[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[N:24][C:25]=2[CH:26]=1)#[N:29]
Reactant: N#Cc1ccc(O)c(N)c1
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C=C(Br)Br
Agent: C1CN2CCN1CC2
Solvent: CN1CCCC1=O
Product: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1Cc1nc2cc(C#N)ccc2o1

Procedure:
A solution of tert-butyl 4-(2,2-dibromovinyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 20-A) (0.720 g, 1.617 mmol) and 3-amino-4-hydroxybenzonitrile (0.325 g, 2.426 mmol) and DABCO (0.544 g, 4.85 mmol) in NMP (1.62 ml) was stirred at 100° C. for 16 hrs. The reaction mixture was cooled and loaded onto silica gel to purify via FCC eluting with Heptane/AcOEt:100/0 to 0/100 to obtain the title compound. MS (ESI+) m/z 418.34 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH3:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([CH:27]=[CH2:28])=[CH:19][N:18]=1.[OH-].[K+]>CN1C(=O)CCC1>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:28][CH2:27][C:20]3[C:21]4[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:17]([CH3:16])=[N:18][CH:19]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=Cc1cnc(C)c2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2cnc(C)c3ccccc23)CCN(C)C1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole, 1-methyl-4-vinylisoquinoline and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][CH2:30][CH2:31][C:32]([F:35])([F:34])[F:33].C(OCC)(=O)C>CN(C=O)C>[F:33][C:32]([F:35])([F:34])[CH2:31][CH2:30][CH2:29][N:2]1[CH2:3][CH2:4][CH2:5][C:6]2[CH:11]=[C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:9]=[CH:8][C:7]=2[CH2:1]1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCNC3)nc1
Reactant: FC(F)(F)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCCN(CCCC(F)(F)F)C3)nc1
Temperature: 95 °C

Procedure:
Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 0.350 g, 1.24 mmol), K2CO3 (0.427 g, 3.09 mmol), and 4-bromo-1,1,1-trifluorobutane (0.248 g, 1.30 mmol) in DMF (6.2 mL). Heat at 95° C. for 5.5 hours, then at 50° C. overnight. Cool the reaction mixture to room temperature and add ethyl acetate (100 mL). Wash with water (1×30 mL) and brine (1×30 mL). Dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography eluting with 6% to 20% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound: MS ES+ 394.2 (M+H)+, HRMS calcd for C20H23N3O2F3 394.1742 (M+H)+, found 394.1733, time 0.53 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TEA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min], tR=10.1 min, 100% purity.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH3:10]>CO>[Cl:1][C:2]1[N:7]=[C:6]([NH2:10])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: N
Solvent: CO
Product: Nc1nc(Cl)ncc1Cl

Procedure:
A solution of 2,4,5-trichloropyrimidine (2.2 ml) in 2M ammonia in methanol (50 ml) was stirred at room temperature overnight. The reaction was then concentrated in vacuo and the resultant solid was washed with water. The residue was triturated with methanol and the solid was isolated by vacuum filtration to furnish the title compound as a white solid (487 mg). 1H NMR (400 MHz, DMSO-d6): 8.18 (1H, s).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].C([O-])(=O)C.[Na+].Br[C:11]1[C:12]([NH:14][C:15](=[O:17])[CH:16]=1)=[O:13]>CO>[CH2:1]([NH:4][C:11]1[C:12]([NH:14][C:15](=[O:17])[CH:16]=1)=[O:13])[CH2:2][CH3:3]
Reactant: CCCN
Reactant: O=C1C=C(Br)C(=O)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CCCNC1=CC(=O)NC1=O
Reaction time: 0.17 h
Yield: 49 %

Procedure:
To propylamine (75 μL, 1.09 mmol) and sodium acetate (92 mg, 1.12 mmol) in methanol (15 mL) was added bromomaleimide (200 mg, 1.12 mmol) dropwise in methanol (15 mL). After 10 minutes, solvent was removed in vacuo and purification by flash chromatography (10% ethyl acetate in petroleum ether) afforded the desired compound as a bright yellow waxy solid (82 mg, 0.53 mmol) in 49% yield. δH (500 MHz, CDCl3) 7.36 (s, 1H, NH), 5.45 (s, 1H, NH), 4.80 (d, 1H, J=1.3, H-5), 3.14 (dt, 2H, J=6.2 and 7.2, H2-3), 1.71-1.63 (m, 2H, H2-2), 0.99 (t, 3H, J=7.4, H3-1); δc (125 MHz, CDCl3) 172.31 (C═O), 167.73 (C═O), 149.83 (C4), 85.29 (C5), 46.16 (C3), 21.91 (C2), 11.42 (C1); IR (solid, cm−1) 3190 (m), 2962 (m), 1693 (m), 1627 (s); MS (EI) m/z (relative intensity): 154 (M+, 60), 125 (98), 84 (100); Exact Mass Calcd for [C7H10N2O2]+ requires m/z 154.0737 Found 154.0734 (EI); UV (Acetonitrile) ε240=7400 and ε348=5700 cm−1M−1 d3.
Reaction SMILES: [N+:1]([C:4]1[C:5]([OH:11])=[N:6][CH:7]=[CH:8][C:9]=1[OH:10])([O-:3])=[O:2].[H-].[Na+].[CH2:14](I)[CH3:15]>CN(C=O)C>[CH2:14]([N:6]1[CH:7]=[CH:8][C:9]([OH:10])=[C:4]([N+:1]([O-:3])=[O:2])[C:5]1=[O:11])[CH3:15]
Reactant: O=[N+]([O-])c1c(O)ccnc1O
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1ccc(O)c([N+](=O)[O-])c1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 53.4 %

Procedure:
To a solution of 3-nitro-pyridine-2,4-diol (1.0 g, 6.41 mmol) in DMF (10 mL) at 0° C., was added NaH (0.51 g, 12.82 mmol 60% in mineral oil). After stirring at 0° C. for 15 min, ethyl iodide (1.10 g, 7.05 mmol) was added and the reaction was stirred at 55° C. for 17 h. After cooling to room temperature, the mixture was poured into ice water, and then filtered to remove insoluble material. The filtrate was acidified with 1 N HCl, extracted with CH2Cl2, dried with MgSO4, and concentrated. The product was rinsed with EtOH to give 1-ethyl-4-hydroxy-3-nitro-1H-pyridin-2-one (0.63 g, 53% yield). 1H-NMR (DMSO): δ, 7.79 (d, 1H, J=7.6 Hz), 6.09 (d, 1H, J=7.6 Hz), 3.90 (q, 2H, J=7.2 Hz), 1.19 (t, 3H, J=7.2 Hz).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[C:11]([NH2:16])=[N:12][CH:13]=[CH:14][CH:15]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[C:17]1([CH2:23][CH2:24][C:25](Cl)=[O:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>N1C=CC=CC=1>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[C:11]([NH:16][C:25](=[O:26])[CH2:24][CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:12][CH:13]=[CH:14][CH:15]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: O=C(Cl)CCc1ccccc1
Reactant: CCOP(=O)(Cc1cccnc1N)OCC
Solvent: c1ccncc1
Product: CCOP(=O)(Cc1cccnc1NC(=O)CCc1ccccc1)OCC
Temperature: 25 °C
Reaction time: 20 h
Yield: 91.2 %

Procedure:
To a solution of diethyl[(2-amino-3-pyridyl)methyl]phosphonate (9.65 g, 39.51 mmol) in pyridine (60 mL) was added 3-phenylpropionyl chloride (7.00 mL, 47.41 mmol) under ice-cooling, and the resulting mixture was stirred at room temperature for 20 hrs. The reaction mixture was concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1-0/1, ethyl acetate/hexane=9/1) to give the title compound (13.56 g, yield 91%) as a brown oil.
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:15]([O:17]CC2C=CC=CC=2)=[O:16])[CH2:4]1)=O.[F:31][C:32]1[CH:33]=[C:34]([CH2:39][CH2:40][CH2:41][CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH:35]=[C:36]([F:38])[CH:37]=1>>[F:31][C:32]1[CH:33]=[C:34]([CH2:39][CH2:40][CH2:41][CH:42]2[CH2:43][CH2:44][N:45]([CH2:1][C@@H:3]3[C@@H:7]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH2:6][N:5]([C@H:14]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[C:15]([OH:17])=[O:16])[CH2:4]3)[CH2:46][CH2:47]2)[CH:35]=[C:36]([F:38])[CH:37]=1
Reactant: Fc1cc(F)cc(CCCC2CCNCC2)c1
Reactant: O=C[C@H]1CN([C@@H](C(=O)OCc2ccccc2)C2CCCCC2)C[C@@H]1c1ccccc1
Product: O=C(O)[C@@H](C1CCCCC1)N1C[C@H](CN2CCC(CCCc3cc(F)cc(F)c3)CC2)[C@@H](c2ccccc2)C1

Procedure:
The title compound was prepared from 2-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, benzyl ester (from EXAMPLE 1, Step I) and 4-(3-(3,5-difluorophenyl)propyl)piperidine.HCl (from EXAMPLE 95, Step E) using procedures analogous to those described in EXAMPLE 1, Steps J and K. For the title compound: 1H NMR (500 MHz, CD3OD) δ 1.14-1.47 (1OH). 1.58-1.68 (6H). 1.77-1.84 (6H). 2.06 (t, J=11.0, 1H), 2.36 (d, J=12.3, 1H), 2.53-2.59 (3H). 2.75-2.81 (2H). 2.96 (d, J=10.5, 1H), 3.11 (q, J=10.5, 1H), 3.30-3.42 (3H). 3.57-3.60 (2H). 6.67-6.72 (m, 1H). 6.74-6.76 (2H). 7.25-7.28 (m, 1H). 7.34-7.89 (4H); ESI-MS 539 (M+H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[Si:13]([O:20][CH2:21]/[CH:22]=[N:23]/[S@:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>C1(C)C=CC=CC=1.[Cl-].[Na+].O>[Si:13]([O:20][CH2:21][C@@H:22]([NH:23][S@:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[S@](=O)/N=C/CO[Si](C)(C)C(C)(C)C
Reactant: Brc1cccnc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)[S@](=O)N[C@H](CO[Si](C)(C)C(C)(C)C)c1cccnc1
Yield: 22.4 %

Procedure:
To a solution of toluene (50 mL) cooled to −78° C. was added 2.5 M butyllithium in hexanes (6.31 mL, 15.1 mmol) and the reaction mixture was stirred until the temperature returned to −78° C. 3-Bromopyridine (1.88 g, 11.9 mmol) in toluene (5 mL) was added to the reaction mixture a rate such that the temperature never went above −65° C., and then the reaction was stirred at −78° C. for 1 hour. (S,E)-N-(2-(tert-Butyldimethylsilyloxy)ethylidene)-2-methylpropane-2-sulfinamide (3.00 g, 10.8 mmol) in toluene (1 mL) was added to the reaction mixture at a rate such that the temperature did not exceed −70° C., and then the reaction was stirred at −78° C. for 2 hours. To the −78° C. solution was added brine and the mixture partitioned between ETOAc/water. The organic layer was washed with brine, dried (phase separator silicone treated filter paper), concentrated and purified on silica gel (15-80% EtOAc in DCM) to provide (S)—N—((S)-2-(tert-butyldimethylsilyloxy)-1-(pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (0.862 g, 22% yield) as a yellow oil.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH:4]([N:7]=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:3][CH2:2]1.[NH2:16][NH2:17]>>[CH:10]1([NH:9][C:8]([NH:16][NH:17][C:8](=[N:7][CH:4]2[CH2:5][CH2:6][CH2:1][CH2:2][CH2:3]2)[NH:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:7][CH:4]2[CH2:3][CH2:2][CH2:1][CH2:6][CH2:5]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: NN
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Product: C1CCC(N=C(NNC(=NC2CCCCC2)NC2CCCCC2)NC2CCCCC2)CC1

Procedure:
DCC (1.03 g, 4.97 mmol) was dissolved in tetrahydrofuran (15 mL). Hydrazine (135 mg, 4.22 mmol) was added via syringe. Stirring 30 hours at room temperature produced a clear yellow mixture which was evaporated to a white powder (922 mg). Solution of this powder in diethyl ether, filtration and acidification with HCl (60 mL of saturated Et2O) gave a yellow white precipitate (856 mg). Two recrystallizations (EtOH in an Et2O chamber) gave white prisms (133 mg, 18%, M.P. 288°-290° C.). The low percentage of nitrogen in the elemental analysis of this compound indicates that two equivalents of DCC have reacted to hydrazine, forming the title compound. 1H NMR ([2H]--CH3OH) δ 3.21 (s, 4, N-bearing cyclohexyl), 2.0-1.5 (m, 44, cyclohexyls). 13C NMR ([2H]--CH3OH) δ 154.1 (guanidine), 51.7 (N-bearing cyclohexyl), 32.4 and 24.8 (cyclohexyls). IR shows peaks at 1639 and 1589 cm-1. Elem. Analysis (C26N6H50Cl2 :1/2 H2O). Theor. C 59.30, H 9.76, N 15.96, Found C 58.94, H 9.76, N 16.01.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]1[CH:13]=[N:14][N:15]3[C:20]([NH2:21])=[CH:19][C:18]([CH:22]([NH:24][CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH3:23])=[N:17][C:16]=13)=[CH:5]2.[H-].[Na+].Br[CH2:34][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]1[CH:13]=[N:14][N:15]3[C:20]([NH:21][CH2:34][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[CH:19][C:18]([CH:22]([NH:24][CH:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)[CH3:23])=[N:17][C:16]=13)=[CH:5]2
Reactant: CC(C)(C)OC(=O)CCBr
Reactant: CC(NC1CCOCC1)c1cc(N)n2ncc(-c3cnc4ccc(F)cc4c3)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(NC1CCOCC1)c1cc(NCCC(=O)OC(C)(C)C)n2ncc(-c3cnc4ccc(F)cc4c3)c2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69.2 %

Procedure:
A stirred solution of 3-(6-fluoroquinolin-3-yl)-5-[1-(tetrahydro-2H-pyran-4-ylamino)ethyl]pyrazolo[1,5-a]pyrimidin-7-amine (240 mg, 0.50 mmol) in anhydrous DMF (6 mL) was treated with sodium hydride (60% suspension in mineral oil, 59 mg, 1.5 mmol) in a single portion under an atmosphere of nitrogen. The resulting yellow-orange slurry was stirred at room temperature for 15 min, and tert-butyl 3-bromopropanoate (128 uL, 0.77 mmol) was added dropwise, gas evolution occurring during the addition. The mixture was stirred at room temperature overnight and was then quenched with water (15 mL) and extracted with EtOAc (2×25 mL). The combined organics were washed with water (3×20 mL) and brine (10 mL), dried over MgSO4, filtered, and concentrated in vacuo and the residue was purified by flash chromatography (40 g silica gel, 3-9% MeOH/DCM) to give tert-butyl 3-(3-(6-fluoroquinolin-3-yl)-5-(1-(tetrahydro-2H-pyran-4-ylamino)ethyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)propanoate (185 mg, 69%) as a glassy solid. MS (ESI+) for C29H35FN6O3 m/z 535 (M+H)+; HPLC, 3.27 min (Method B).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[S:21][N:20]=2)[CH2:15][CH2:14]1)([O-])=O.C(N(CC)CC)C>C1COCC1.[Ni]>[S:21]1[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:19]([N:16]2[CH2:17][CH2:18][N:13]([CH2:12][CH2:11][CH2:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[NH2:1])[CH2:14][CH2:15]2)=[N:20]1
Reactant: O=[N+]([O-])c1ccccc1CCCN1CCN(c2nsc3ccccc23)CC1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ccccc1CCCN1CCN(c2nsc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78 %

Procedure:
3-{4-[3-(2-Nitro-phenyl)-propyl]-piperazin-1-yl}-1,2-benzoisothiazole (3.25 g, 8.5 mmol) was dissolved in 100 mL of THF treated with triethylamine (0.3 ml) and with wet Raney nickel (1.02 g). The resulting mixture was placed on a shaker type hydrogenator, purged with hydrogen, pressurized (29.8 psig) and shaken at room temperature for 16 hours. The resulting mixture was filtered to remove the catalyst then filtered a second time over celite before the filtrate was concentrated. The resultant solid was dried in vacuo (2.33 g, 6.61 mmol). Yield 78%; MS (APCI): 352 [M+H]+.
Reaction SMILES: Cl.[OH:2][C:3]1[C:4]([O:27][CH3:28])=[C:5]([C:10](=[O:26])[CH2:11][NH:12][C:13]([CH3:25])([CH3:24])[CH2:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[CH:6]=[CH:7][C:8]=1[OH:9]>CO.[Pt](=O)=O>[CH3:25][C:13]([NH:12][CH2:11][CH:10]([C:5]1[C:4]([O:27][CH3:28])=[C:3]([OH:2])[C:8]([OH:9])=[CH:7][CH:6]=1)[OH:26])([CH3:24])[CH2:14][C:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=1[CH3:23]
Reactant: COc1c(C(=O)CNC(C)(C)Cc2c(C)cc(C)cc2C)ccc(O)c1O
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: COc1c(C(O)CNC(C)(C)Cc2c(C)cc(C)cc2C)ccc(O)c1O

Procedure:
9 g of 1-(3,4-dihydroxy-2-methoxyphenyl)-2-[1,1-dimethyl-2-(2,4,6-trimethylphenyl)-ethylamino]ethanone hydrochloride is hydrogenated with 0.4 g of platinum(IV) oxide in 125 mL of methanol. The catalyst is filtered off and the solvent is distilled off under reduced pressure. The residue is dissolved in 50 mL of ethyl acetate and the precipitated crystals are suction filtered and washed with diethyl ether and ethyl acetate. Yield: 6 g (67%, hydrochloride); melting point: 98° C.-105° C.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:11]([O:18][CH3:19])=[N:12][CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][C:22]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1>>[CH3:19][O:18][C:11]1[C:10]([CH:2]2[N:1]([CH2:25][C:24]3[CH:27]=[CH:28][C:21]([F:20])=[C:22]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[CH:23]=3)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]2)=[C:15]([O:16][CH3:17])[CH:14]=[CH:13][N:12]=1
Reactant: O=Cc1ccc(F)c(-c2ccccn2)c1
Reactant: COC(=O)CCCC(N)c1c(OC)ccnc1OC
Product: COc1ccnc(OC)c1C1CCCC(=O)N1Cc1ccc(F)c(-c2ccccn2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,4-dimethoxypyridin-3-yl)pentanoate with 4-fluoro-3-(pyridin-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.58 min.; [M+H]+: 421.83 g/mol.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([S:16]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:13][C@H:12]1[CH2:36][NH2:37])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:38][C:39]1[CH:46]=[CH:45][C:44]([F:47])=[CH:43][C:40]=1[CH:41]=O>>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([SH:16])[CH2:13][C@H:12]1[CH2:36][NH:37][CH2:41][C:40]1[CH:43]=[C:44]([F:47])[CH:45]=[CH:46][C:39]=1[F:38])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc(F)ccc1F
Reactant: NC[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccccc1
Product: O=C(OCc1ccccc1)N1C[C@H](S)C[C@H]1CNCc1cc(F)ccc1F

Procedure:
(2S,4R)-2-aminomethyl-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid benzyl ester and 2,5-difluorobenzaldehyde and subsequent cleavage of the trityl protecting group analogously to reductive amination and deprotection gave (2S,4R)-2-[(2,5-difluoro-benzylamino)-methyl]-4-mercapto-pyrrolidine-1-carboxylic acid benzyl ester as colorless oil, MS: 393 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[O:10][C:9]=2[C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.Cl[CH2:36][C:37]1[N:38]=[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]2[CH:45]=1>O>[N:38]1[C:37]([CH2:36][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:12](=[O:13])[C:11]([CH3:14])([CH3:15])[O:10][C:9]=3[C:16]3[CH:17]=[CH:18][C:19]([C:20]#[N:21])=[CH:22][CH:23]=3)=[CH:6][CH:7]=2)=[CH:45][N:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=12
Reactant: ClCc1cn2ccccc2n1
Reactant: CC1(C)OC(c2ccc(C#N)cc2)=C(c2ccc(O)cc2)C1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OC(c2ccc(C#N)cc2)=C(c2ccc(OCc3cn4ccccc4n3)cc2)C1=O
Temperature: 80 °C
Yield: 60.2 %

Procedure:
4-(3-(4-Hydroxyphenyl)-5,5-dimethyl-4-oxo-4,5-dihydro furan-2-yl)benzonitrile (3.15 g, 10.3 mmol) was added to a mixture of cesium carbonate (13.4 g, 41.3 mmol) and DMF (100 mL) at RT under an atmosphere of nitrogen. The reaction mixture was stirred at RT for 30 min upon which 2-(chloromethyl)imidazo[1,2-a]pyridine (2.0 g, 12.3 mmol) was added. The mixture was heated at 80° C. for 4 h (the reaction was monitored by TLC). The reaction mixture was diluted with water and extracted with EtOAc, the combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 20% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford 4-(3-(4-(imidazo[1,2-a]pyridin-2-ylmethoxy)phenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile (2.7 g, 60%) as an off-white solid. 1H NMR: 500 MHz, DMSO-d6: δ 8.55 (d, 1H), 8.0 (s, 1H), 7.55 (Ar, 3H), 7.3-6.85 (Ar, 8H), 5.15 (s, 2H), 1.25 (s, 6H). MS: [M+H]+: m/z=436.2. HPLC: (97.3%, Condition-A).
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[C:9]([O:14][CH:15]([C:17]2[C:22]([Cl:23])=[CH:21][CH:20]=[C:19]([F:24])[C:18]=2[Cl:25])[CH3:16])[C:10]([NH2:13])=[N:11][CH:12]=1)(C)C.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CO>[C:6]([C:7]1[CH:8]=[C:9]([O:14][CH:15]([C:17]2[C:22]([Cl:23])=[CH:21][CH:20]=[C:19]([F:24])[C:18]=2[Cl:25])[CH3:16])[C:10]([NH2:13])=[N:11][CH:12]=1)#[CH:5]
Reactant: CC(Oc1cc(C#C[Si](C)(C)C)cnc1N)c1c(Cl)ccc(F)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: C#Cc1cnc(N)c(OC(C)c2c(Cl)ccc(F)c2Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.3 %

Procedure:
5-trimethylsilylethynyl-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-2-aminopyridine (1.5 g, 3.77 mmol) was dissolved in the mixed solvent of THF (10 mL) and MeOH (10 mL), K2CO3 (1.04 g, 7.55 mmol) was added, and the mixture was stirred for 2 h at room temperature. The majority of the solvent was removed under reduced pressure, water (10 mL) was added. The resultant mixture was extracted with ethyl acetate (3×20 mL), the organic phases were combined, washed with water and saturated brine successively, dried over anhydrous sodium sulfate, and then concentrated, the resultant residue was purified via silica gel column chromatography (petroleum ether/ethyl acetate=3:1) to yield 850 mg of the target product as brown solid.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.Cl[C:8]1[S:9][C:10]([N+:14]([O-:16])=[O:15])=[C:11]([Cl:13])[N:12]=1>CN1CCCC1=O>[Cl:13][C:11]1[N:12]=[C:8]([N:4]2[CH:5]=[CH:6][C:2]([CH3:1])=[N:3]2)[S:9][C:10]=1[N+:14]([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1sc(Cl)nc1Cl
Reactant: Cc1cc[nH]n1
Solvent: CN1CCCC1=O
Product: Cc1ccn(-c2nc(Cl)c([N+](=O)[O-])s2)n1
Temperature: 0 °C
Reaction time: 96 h
Yield: 94.8 %

Procedure:
4.1 g (0.05 mol) of 3-methylpyrazole are added to a solution of 5.0 g (0.025 mol) of 2,4-dichloro-5-nitrothiazole in 50 ml of N-methyl-2-pyrrolidinone at room temperature. After the mixture has been left to stand at room temperature for four days, it is stirred into 500 ml of ice-water and the precipitate is filtered off, washed with water and dried. 5.8 g (94.9% of theory) of 4-chloro-2-(3-methyl-1-pyrazolyl)-5-nitrothiazole of melting point 153° C. are obtained.