Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]([OH:7])=[O:6])([OH:3])=[O:2].[C:8]([O:12][C:13]([NH:15][C:16]1[C:17]([C:36]2[CH:44]=[CH:43][C:39]([C:40]([O-:42])=[O:41])=[C:38]([F:45])[CH:37]=2)=[N:18][C:19]([CH:22]2[CH2:27][CH2:26][C:25]([O:28][Si](CC)(CC)CC)=[CH:24][CH2:23]2)=[CH:20][N:21]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9].[B-](F)(F)(F)[F:47].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C>[C:1]([NH:4][C:5]([OH:7])=[O:6])([OH:3])=[O:2].[C:8]([O:12][C:13]([NH:15][C:16]1[C:17]([C:36]2[CH:44]=[CH:43][C:39]([C:40]([O-:42])=[O:41])=[C:38]([F:45])[CH:37]=2)=[N:18][C:19]([CH:22]2[CH2:23][CH2:24][C:25](=[O:28])[CH:26]([F:47])[CH2:27]2)=[CH:20][N:21]=1)=[O:14])([CH3:9])([CH3:11])[CH3:10]
Reactant: F[B-](F)(F)F
Reactant: CC[Si](CC)(CC)OC1=CCC(c2cnc(NC(=O)OC(C)(C)C)c(-c3ccc(C(=O)[O-])c(F)c3)n2)CC1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: O=C(O)NC(=O)O
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1ncc(C2CCC(=O)C(F)C2)nc1-c1ccc(C(=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of imidodicarbonic acid, 4-(3-((tert-butoxycarbonyl)amino)-6-(4-((triethylsilyl)oxy)cyclohex-3-en-1-yl)pyrazin-2-yl)-2-fluorobenzoate, 1,3-bis(1,1-dimethylethyl) ester (12.1 g, 17.29 mmol) in acetonitrile (57.6 mL) was added Selectfluor® (7.96 g, 22.47 mmol) at 0° C. The reaction mixture was warmed up to room temperature and stirred overnight. After quenched with sat. NaHCO3 solution, the reaction mixture was extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo to provide imidodicarbonic acid, 4-(3-((tert-butoxycarbonyl)amino)-6-(3-fluoro-4-oxocyclohexyl)pyrazin-2-yl)-2-fluorobenzoate, 1,3-bis(1,1-dimethylethyl) ester (10.44 g, 17.29, 100%), which was used for the next step without further purification. LCMS (m/z, neutral-nonpolar method): 604.3 (MH+), 1.12 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][CH2:11][C:12](=O)[CH3:13])=[CH:5][CH:4]=1.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][NH2:25])=[CH:19][CH:18]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][N:25]2[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:19][CH:18]=1
Reactant: NCCc1ccc(Br)cc1
Reactant: COc1ccc(C(=O)CCC(C)=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccc(C)n2CCc2ccc(Br)cc2)cc1
Yield: 68 %

Procedure:
A solution of 1-(4-methoxyphenyl)-1,4-pentanedione (3.20 g, 15.5 mol), 2-(4-bromophenyl)ethylamine (3.74 g, 18.7 mmol) and p-toluenesulfonic acid monohydrate (150 mg, 0.871 mmol) in toluene (100 ml) was refluxed for 20 hours with heating. The insoluble matter was filtered out and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:1) to give the object compound as an oily substance. 3.93 g (yield: 68.0%)
Reaction SMILES: [CH2:1]([O:5][CH2:6][C:7]1[C:8]([O:14][CH3:15])=[N:9][CH:10]=[CH:11][C:12]=1I)[CH:2]=[CH:3][CH3:4].C(=O)([O-])[O-].[K+].[K+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Rh]Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:3]([C:2]1[C:12]2[C:7](=[C:8]([O:14][CH3:15])[N:9]=[CH:10][CH:11]=2)[CH2:6][O:5][CH:1]=1)[CH3:4]
Reactant: CC=CCOCc1c(I)ccnc1OC
Agent: Cl[Rh]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: CCC1=COCc2c1ccnc2OC
Temperature: 90 °C

Procedure:
A mixture of 3-(but-2-enyloxymethyl)-4-iodo-2-methoxy-pyridine (228 g, 0.714 mol), potassium carbonate (200 g, 1.45 mol) and tetrabutylammonium chloride (100 g, 0.36 mol) in N,N-dimethylformamide (3.5 L) is purged with nitrogen for 20 min prior to the addition of palladium(II) acetate (3.75 g, 0.0167 mol) and tris(triphenylphosphine) rhodium(I) chloride (5.31 g, 0.00574 mol). The mixture is heated at 90° C. for about 4 h, cooled to below 50° C. and filtered through a pad of Celite®. The pad is washed with tert-butyl methyl ether (200 ml). The filtrate is washed with water (4×3 L), dried over sodium sulfate (260 g) and concentrated to a dark oil that is vacuum distilled (about 85°-98° C., about 6 mm Hg) to provide 4-ethyl-8-methoxy-1H-pyrano[3,4-c]pyridine as a yellow-orange oil which contains a 14.3:1 ratio of 4-ethyl-8-methoxy-1H-pyrano[3,4-c]pyridine to the corresponding double bond isomer, 4-ethylidene-8-methoxy-3,4-dihydro-1H-pyrano[3,4-c]pyridine.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[C:4](=[O:34])[C:3]1=[N:35]NC1C=CC=CC=1>[Zn].C(O)(=O)C>[NH2:35][CH:3]1[C:2](=[O:1])[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[C:4]1=[O:34]
Reactant: COc1ccc(N(C(=O)Cn2c(=O)c(=NNc3ccccc3)c(=O)n(-c3ccccn3)c3ccccc32)C(C)C)cc1
Agent: [Zn]
Solvent: CC(=O)O
Product: COc1ccc(N(C(=O)CN2C(=O)C(N)C(=O)N(c3ccccn3)c3ccccc32)C(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.7 %

Procedure:
A mixture of 2-[2,4-Dioxo-3(phenyl-hydrazono)-5-pyrdin-2-yl-2,3,4,5-tetrahydrobenzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-(4-methoxy-phenyl)-acetamide (460 mg), zinc dust (430 mg) and acetic acid (5.6 ml) was stirred at rt for 3 h. The solids were removed by filtration through celite, the filtrate was concentrated in vacuo and the residue azeotroped with hexane. The residue was dissolved in ethyl acetate (50 ml) and washed with 2N aqueous sodium bicarbonate (2×30 ml), water, (30 ml), brine (30 ml), dried (MgSO4) and concentrated in vacuo to afford the crude product (270 mg) which was used without further purification. 1H NMR (300 MHz, CDCl3); 1.03 (d, J=7 Hz, 6H), 3.79 (s, 3H), 4.02 (d J=10 Hz, 1H), 4.40 (s, 1H), 4.42 (d, J=10 Hz, 1H), 5.0 (sept, J=7.1 Hz, 1H), 6.8-7.3 (m, 10H), 7.44 (d, J=8.0 Hz 1H), 7.68 (d, J=8.0 Hz, 1H), 7.80 (m, 1H), 8.42 (d, J=3.9 Hz, 1H). Tlc (10% MeOH, CH2Cl2) Rf=0.23.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][C@H:4]([CH3:17])[C@:5]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)(O)[CH2:6][CH3:7].S(=O)(=O)(O)O.CS(O)(=O)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C1CCCCC1.O1CCCC1>[CH3:16][O:15][C:11]1[CH:10]=[C:9]([C@H:5]([CH2:6][CH3:7])[C@@H:4]([CH3:17])[CH2:3][N:2]([CH3:18])[CH3:1])[CH:14]=[CH:13][CH:12]=1
Reactant: CC[C@](O)(c1cccc(OC)c1)[C@@H](C)CN(C)C
Agent: CS(=O)(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: C1CCCCC1
Solvent: O
Solvent: C1CCOC1
Product: CC[C@@H](c1cccc(OC)c1)[C@@H](C)CN(C)C
Temperature: 20 °C

Procedure:
Accordingly the compound (2S,3R)-1-(dimethylamino)-3-(3-methoxyphenyl)-2-methyl pentan-3-ol of Formula-V was charged in the solvent tetrahydrofuran and under stirring charged concentrated sulfuric acid at temperature of 20-30° C. The reaction mixture is stirred and charged methanesulfonic acid or para toluenesulfonic acid and solvent cyclohexane. Stirred and raised the temperature to reflux. Maintained the reaction mass at reflux temperature for 3-5 hours with simultaneous removal of water. Cooled the reaction mass to 20° C. and separated the organic layer. Charged the organic layer in an autoclave and diluted the layer with tetrahydrofuran. Charged the catalyst Pd/C. Purged the autoclave with nitrogen gas and followed with hydrogen gas pressure of 5-7 kg. Maintained the reaction mass at 25-30° C. for 2-4 hours. After completion of the reaction the reaction mass was filtered and the filtrate was concentrated under reduced pressure to get the residual mass. Diluted the residual mass with water and extracted with toluene. Separated the aqueous layer and adjusted the pH to 9-10 with aqueous solution of sodium hydroxide. Extracted the aqueous layer with diisopropyl ether, separated the organic layer and concentrated under reduced pressure below 40° C. to get the compound (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine of Formula-VII.
Reaction SMILES: [H-].[Na+].Br[CH:4]([CH3:8])[C:5]([OH:7])=[O:6].[F:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1>COCCOC>[F:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH:4]([CH3:8])[C:5]([OH:7])=[O:6])=[CH:12][CH:11]=1
Reactant: Oc1ccc(F)cc1
Reactant: CC(Br)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(Oc1ccc(F)cc1)C(=O)O
Yield: 60.3 %

Procedure:
To a stirred slurry of 8.3 g of sodium hydride (57° 10 NaH in oil) in 100 ml of dry 1,2-dimethoxyethane at 5° C. is added 15.3 g of 2-bromopropionic acid in 50 ml of 1,2-dimethoxyethane and 10.5 g of 4-fluorophenol in 50 ml of 1,2-dimethoxyethane. The mixture is refluxed for 6 hrs, cooled and filtered. The solid is partitioned between dichloromethane and 1N HCl. The organic layer is dried (MgSO4) and concentrated to 50 ml. The mixture is filtered to give 10.4 g of product, mp 113°-115° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[N:21]1([C:27]2[CH:32]=[C:31]([CH:33]=O)[CH:30]=[CH:29][N:28]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C([O-])(=O)C.[NH4+]>>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:33]([C:31]3[CH:30]=[CH:29][N:28]=[C:27]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH:32]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: O=Cc1ccnc(N2CCOCC2)c1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc3[nH]c(-c4ccnc(N5CCOCC5)c4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 86.5 %

Procedure:
In a similar fashion to Compound CXXV, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (57.57 mg, 0.1702 mmol), 2-Morpholin-4-yl-pyridine-4-carbaldehyde (36.0 mg, 0.187 mmol), and Ammonium acetate (26.2 mg, 0.340 mmol) were reacted to produce 75.1 mg (86%) of the title compound. (300 MHz, DMSO-d6) 13.47 (s, 1H), 8.28 (d, J=5 Hz, 1H), 8.08 (s, 1H), 7.76 (s, 1H), 7.52 s, 1H), 7.36 (d, J=5 Hz, 1H), 7.33 (d, J=8 Hz, 1H), 7.24 (s, 1H), 6.39 (s, 2H), 5.20 (t, J=17 Hz, 8.5 Hz, 1H), 3.75 (m, 4H), 3.54 (s, 4H), 2.90 (s, 1H), 2.79 (s, 1H), 2.62 (d, J=8 Hz, 1H), 2.24 (d, J=8 Hz, 1H), 1.38 (d, J=8 Hz, 1H). MS=512 (M+H), HPLC: 1.78 min. (G Method)
Reaction SMILES: C(O[C:4](=[O:20])[C:5](=[CH:11][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15](C)[N:14]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[CH3:21]CCCCC>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:9]([O:8][C:6]([C:5]1[C:4](=[O:20])[C:18]2[C:13](=[N:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH3:21])[CH:11]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)C(=CNc1cccc(C)n1)C(=O)OCC
Reactant: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cn(C)c2ncccc2c1=O
Temperature: 250 °C

Procedure:
21.8 g (3.61 mmol) of 2-[(6-Methyl-pyridin-2-ylamino)-methylene]-malonic acid diethyl ester was dissolved in 300 mL of diphenyl ether and the solution was heated at 250° C. After 2.5 h the solution was cooled to rt and 50 mL of hexane was added. The mixture was filtered and the solid washed with hexane to yield 18.5 g of -Methyl-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid ethyl ester as a brown solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH2:18][CH2:19][C:20](O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C.Cl.[O:44]1[C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=2[O:47][CH2:46][CH:45]1[CH2:54][NH2:55]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH2:18][CH2:19][CH2:20][NH:55][CH2:54][CH:45]1[O:44][C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=2[O:47][CH2:46]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1c[nH]c2ccc(OCc3ccccc3)cc12
Reactant: NCC1COc2ccccc2O1
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(COc2ccc3[nH]cc(CCCNCC4COc5ccccc5O4)c3c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
5-Benzyloxyindole-3-propionic acid (2.7 g, 9.1 mmole), 1-hydroxybenzotriazole hydrate (1.5 g, 10.9 mmole) and 1,3-diisopropylcarbodiimide (3.4 ml, 21.8 mmole) were combined in 200 ml of DMF and stirred at room temperature for 2 hours under a nitrogen atmosphere. To this was added dropwise 2,3-dihydro-1,4-benzodioxin-2-methanamine hydrochloride (1.8 g, 9.1 mmole) in 50 ml of DMF and the mixture was further stirred for 24 hours. The solvent was removed and replaced with dichloromethane. The mixture was then washed with H2O. The separated organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was chromatographed on silica gel using first dichloromethane and then 2.5% methanol in dichloromethane as eluants to give 3.2 g (79%) of the desired product, (2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-3-(5-benzyloxy-1H-indol-3-yl)-propanamide, as a light tan solid.
Reaction SMILES: I(O)(=O)(=O)=[O:2].[F:6][C:7]([F:36])([F:35])[CH2:8][CH2:9][C@H:10]([NH:13][C@@H:14]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)[C:15]([F:18])([F:17])[F:16])[CH2:11][OH:12]>C(#N)C.[O-2].[O-2].[O-2].[Cr+6]>[F:36][C:7]([F:6])([F:35])[CH2:8][CH2:9][C@H:10]([NH:13][C@@H:14]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:32])=[O:33])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)[C:15]([F:16])([F:17])[F:18])[C:11]([OH:2])=[O:12]
Reactant: CS(=O)(=O)c1ccc(-c2ccc([C@H](N[C@H](CO)CCC(F)(F)F)C(F)(F)F)cc2)cc1
Reactant: [O-][I+3]([O-])([O-])O
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(-c2ccc([C@H](N[C@@H](CCC(F)(F)F)C(=O)O)C(F)(F)F)cc2)cc1
Temperature: 2.5 °C
Reaction time: 4 h

Procedure:
A stock oxidant suspension was prepared by stirring periodic acid (2.28 g) and chromium trioxide (4.6 mg) in wet acetonitrile (0.75% water) to create a suspension of total volume of 22.8 mL. The oxidant suspension (4.22 mL) was then added to a stirred solution of (2S)-5,5,5-trifluoro-2-({(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl}amino)pentan-1-ol (0.35 g, 0.74 mmol) in wet acetonitrile (3.7 mL) dropwise while maintaining the temperature at 0-5° C. The reaction mixture was allowed to warm to ambient temperature after one hour and then stirred for an additional 4 hours. The reaction was quenched with aqueous sodium hydrogen phosphate (6 g/100 mL) and toluene was added and the mixture shaken vigorously. The organic phase was washed with 1:1 brine:water, then with aqueous sodium bisulfite (2.2 g/50 mL), then brine. The organic layer was then dried with sodium sulfate, filtered, and concentrated by rotary evaporation. The crude product was purified by silica gel chromatography using 5-10% methanol in methylene chloride as eluant to yield (2S)-5,5,5-trifluoro-2-({(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl}amino)pentanoic acid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH3:11][O:12][CH:13]([O:26][CH3:27])[C:14]1[C:23]([CH:24]=O)=[CH:22][C:21]2[CH2:20][CH2:19][CH2:18][NH:17][C:16]=2[N:15]=1.CCN(CC)CC.[BH4-].[Na+]>CC(N(C)C)=O.CO>[CH3:27][O:26][CH:13]([O:12][CH3:11])[C:14]1[C:23]([CH2:24][NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:22][C:21]2[CH2:20][CH2:19][CH2:18][NH:17][C:16]=2[N:15]=1
Reactant: COC(OC)c1nc2c(cc1C=O)CCCN2
Reactant: CCOC(=O)CSCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Solvent: CO
Product: CCOC(=O)CSCCNCc1cc2c(nc1C(OC)OC)NCCC2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of ethyl 2-((2-aminoethyl)thio)acetate (intermediate 210, 675 mg, 2.87 mmol) in DMA (7.5 ml) and MeOH (7.5 ml) was added to a solution of 2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridine-3-carbaldehyde (intermediate 41, 710 mg, 3.01 mmol) and Et3N (0.417 mL, 3.01 mmol) in MeOH (7.5 ml) and the reaction mixture was stirred at room temperature for 3 days. NaBH4 (142 mg, 3.75 mmol) was added portion wise and stirring was continued for 40 min at room temperature. Additional Et3N (500 μL, 3.61 mmol) was added and mixture was stirred for 4 h. Solvents were concentrated and the residue was partitioned between DCM and aqueous citric acid (5%). The aqueous layer was extracted with DCM (3×) and the combined organic layers were washed with aqueous citric acid (5%) (3×). The pH value of the combined water layers was adjusted to 9 using aqueous Na2CO3 and the water phase was back extracted with DCM (3×). The organic layers were combined, dried using Na2SO4, filtered and evaporated to yield the title compound as an orange oil. (UPLC-MS 3) tR 0.61 min; ESI-MS 384.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ 7.16 (s, 1H), 6.40-6.36 (m, 1H), 5.08 (s, 1H), 4.12-4.05 (m, 2H), 3.61 (s, 2H), 3.36-3.21 (m, 10H), 2.71-2.61 (m, 6H), 1.80-1.72 (m, 2H), 1.19 (t, 3H
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]#[CH:21])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.Br[C:23]1[S:27][C:26]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]#[C:21][C:23]4[S:27][C:26]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:25][CH:24]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12
Reactant: NS(=O)(=O)c1ccc(Br)s1
Product: NS(=O)(=O)c1ccc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(Cl)cc4)nc23)s1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-cyclopropyl-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.5) (73 mg, 0.25 mmol) and 5-bromo-thiophene-2-sulfonic acid amide (61 mg, 0.25 mmol) according to general procedure II. Obtained as a yellow solid (52 mg, 45%). MS (ISP) 445.4 [(M+H)+]; mp 218-220° C.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:42]=[CH:41][C:12]([C:13]([NH:15][NH:16][C:17](=O)[C@H:18]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[C:32]([Cl:38])[C:31]=2[CH3:39])[C@@H:19]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH3:20])=[O:14])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.[Si](O[C@@H](C)[C@@H](NC1C=CC(C#N)=C(Cl)C=1C)C1OC(C2C=CC=C(O[Si](C(C)(C)C)(C)C)C=2)=NN=1)(C(C)(C)C)(C)C>>[Si:22]([O:21][C@@H:19]([CH3:20])[C@@H:18]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[C:32]([Cl:38])[C:31]=1[CH3:39])[C:17]1[O:14][C:13]([C:12]2[CH:41]=[CH:42][C:9]([O:8][Si:1]([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2])=[CH:10][CH:11]=2)=[N:15][N:16]=1)([C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:23])[CH3:24]
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(O[Si](C)(C)C(C)(C)C)cc2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: Cc1c(N[C@@H](c2nnc(-c3cccc(O[Si](C)(C)C(C)(C)C)c3)o2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)o2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl

Procedure:
Dehydrative cyclization of 4-(tert-butyldimethylsilyloxy)-N′-((2R,3S)-3-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)butanoyl)benzohydrazide (intermediate 8b) (453 mg, 0.72 mmol) with performed with polystyrene supported triphenylphosphine (PS-PPh3) (3.0 mmol/g, 575 mg, 1.72 mmol), I2 (435 mg, 1.71 mmol), and TEA (0.8 mL, 5.7 mmol) as described in the preparation of intermediate 7c. After column chromatography (30% EtOAc/hexanes) the title compound was isolated as a white solid (329 mg, 75%). 1H NMR (500 MHz, CDCl3, δ in ppm) 7.81 (AA′XX′, J=8.7 Hz, 2H), 7.32 (d, J=8.6 Hz, 1H), 6.91 (AA′XX′, J=8.8 Hz, 2H), 6.47 (d, J=8.7 Hz, 1H), 5.35 (d, J=8.7 Hz, 1H), 4.77 (m, 1H), 4.52 (m, 1H), 2.36 (s, 3H), 1.40 (d, J=6.2 Hz, 3H), 0.98 (s, 9H), 0.86 (s, 9H), 0.22 (s, 6H), 0.06 (s, 3H), −0.18 (s, 3H).
Reaction SMILES: [CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]([NH2:18])=[N:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:23][C:24]([CH:26]1[CH2:30][CH2:29][CH2:28][C:27]1=O)=O)C>>[CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][CH:13]3[O:17][C:16]4[N:15]([C:27]5[CH2:28][CH2:29][CH2:30][C:26]=5[C:24](=[O:23])[N:18]=4)[CH2:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NC1=NC[C@@H](COc2ccc(C3CCCCC3)cc2)O1
Reactant: CCOC(=O)C1CCCC1=O
Product: O=c1nc2n(c3c1CCC3)CC(COc1ccc(C3CCCCC3)cc1)O2

Procedure:
The title compound was prepared from (S)-5-(4-cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine and 2-oxo-cyclopentanecarboxylic acid ethyl ester in accordance with the procedures of O.-S. Adetchessi, et. al., Tetrahedron, 61, (2005), 4453-4460. C22H26N2O3 (366.19), LCMS (ESI): 367.16 (M++H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:15])=[C:4]([C@@H:8]2[CH2:10][C@H:9]2[C:11](OC)=[O:12])[CH:5]=[CH:6][CH:7]=1.[BH4-].[Li+]>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:15])=[C:4]([C@@H:8]2[CH2:10][C@H:9]2[CH2:11][OH:12])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H]1C[C@H]1c1cccc(Cl)c1C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(Cl)cccc1[C@@H]1C[C@H]1CO
Temperature: 25 °C
Reaction time: 72 h
Yield: 62.5 %

Procedure:
To a solution of trans-methyl 2-(3-chloro-2-methylphenyl)cyclopropanecarboxylate (0.042, 0.187 mmol) in THF (2.0 mL) was added 2.0 M lithium borohydride (0.467 ml, 0.935 mmol) dropwise at room temperature. The reaction was stirred at room temperature for 3 d. The mixture was partitioned between EtOAc and 1 N HCl. The organic layer separated, and the aqueous phase was extracted with EtOAc. The combined organic layer was dried (MgSO4) and concentrated to afford the title compound (23 mg, 63% yield) as pale-yellow oil. 1H NMR (500 MHz, CDCl3) δ 7.23 (d, J=8.0 Hz, 1H), 7.04 (t, J=7.7 Hz, 1H), 6.96 (d, J=8.0 Hz, 1H), 3.86-3.65 (m, 2H), 2.53-2.45 (m, 3H), 1.90-1.82 (m, 1H), 1.39 (d, J=5.2 Hz, 1H), 0.97-0.90 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]([CH3:16])[CH:13]=[N:14][CH:15]=3)[S:10][C:3]=12.[CH3:17][C:18]1[NH:19][C:20]2[C:25]([CH:26]=1)=[CH:24][C:23]([NH2:27])=[CH:22][CH:21]=2.ClC(Cl)C>C(O)(C)(C)C>[CH3:16][N:12]1[C:11]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[NH:27][C:23]3[CH:24]=[C:25]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([CH3:17])=[CH:26]4)[CH:8]=2)=[CH:15][N:14]=[CH:13]1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: Cn1cncc1-c1cc2nccc(Cl)c2s1
Solvent: CC(Cl)Cl
Solvent: CC(C)(C)O
Product: Cc1cc2cc(Nc3ccnc4cc(-c5cncn5C)sc34)ccc2[nH]1
Yield: 16.5 %

Procedure:
7-Chloro-2-(3-methyl-3H-imidazol-4-yl)-thieno[3,2-b]pyridine (600 mg, 2.40 mmol) and 2-methyl-5-aminoindole (422 mg, 2.89 mmol) were dissolved in 20 mL of tert-butanol and 20 mL of dichloroethane and heated to 85° C. The solvent was allowed to evaporate overnight and was replaced the following day with the same amounts as in the initial reaction mixture along with an additional 90 mg of the indole. The solution was heated an additional 24 hours and allowed to go dry as before. Chromatography of the residue with 30-5-% methanol:ethyl acetate afforded 142 mg (16%) of [2-(3-methyl-3H-imidazol-4-yl)-thieno[3,2-b]pyridin-7-yl]-(2-methyl-1H-indol-5-yl)-amine. 1H NMR (400 MHz, CD3OD) δ8.14 (d, 1H), 7.79 (s, 1H), 7.75 (s, 1H), 7.40 (s, 1H), 7.34 (d, 1H), 7.29 (s, 1H), 6.99 (d, 1H), 6.72 (d, 1H), 6.17 (s, 1H), 3.84 (s, 3H), 2.44 (s, 3H). LC-MS: 360, 361 (MH+); HPLC RT: 3.96 min.