Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[CH2:11][C:10]([CH3:15])([CH3:14])[C:9]2=[O:16])=[N:6][CH:7]=1.CO.[BH4-].[Na+]>C1COCC1>[OH:16][CH:9]1[N:8]([C:5]2[CH:4]=[CH:3][C:2]([I:1])=[CH:7][N:6]=2)[C:12](=[O:13])[CH2:11][C:10]1([CH3:15])[CH3:14]
Reactant: CC1(C)CC(=O)N(c2ccc(I)cn2)C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)CC(=O)N(c2ccc(I)cn2)C1O
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
(800 mg, 2.42 mmol) 1-(5-Iodopyridin-2-yl)-3,3-dimethylpyrrolidine-2,5-dione (Example 13, step 1) was dissolved in THF (6 ml) and MeOH (2 ml) and the solution was cooled to 0-5° C. NaBH4 (101 mg, 2.67 mmol, 1.1 equiv.) was added at 0-5° C. and the mixture was stirred for 1 hr at 0-5° C. The reaction mixture was extracted with sat. NaHCO3 solution and two times with a small volume of dichloromethane. The crude product was purified by flash chromatography by directly loading the dichloromethane layers onto a amino-silica gel column and eluting with a ethyl acetate/heptane gradient, 0:100 to 100:0. The desired (5-RS)-5-hydroxy-1-(5-iodo-pyridin-2-yl)-4,4-dimethyl-pyrrolidin-2-one (370 mg, 46% yield) was obtained as a white solid, MS: m/e=333.0 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:35]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:37]=1)[NH2:34].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:36]1[CH:37]=[C:31]([O:30][CH3:29])[CH:32]=[C:33]([NH2:34])[CH:35]=1
Reactant: COc1cc(N)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cc(N)cc(-c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 53 %

Procedure:
To a solution of (S)-2-(1-((6-amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (150 mg, 0.34 mmol) were added (3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (86 mg, 0.34 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (27 mg, 0.03 mmol) and 340 μl of a 2M aqueous solution of cesium carbonate in dioxane (2 ml). The mixture was stirred under argon atmosphere at 100° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude was purified by reverse phase using SP1® Purification System to give 87 mg (52% yield) of the title compound as a white solid. Purity 98%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[CH:14][C:13]=2[CH2:26][CH2:27][CH3:28])[OH:11])=[C:4]([F:29])[C:3]=1[Si](C)(C)C.C[N+]1([O-])CCOCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl.C(OCC)C.C1COCC1.C(OCC)(=O)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([O:18][C:15]2[CH:16]=[CH:17][C:12]([C:10]([C:5]3[CH:6]=[C:7]([O:8][CH3:9])[C:2]([Cl:1])=[CH:3][C:4]=3[F:29])=[O:11])=[C:13]([CH2:26][CH2:27][CH3:28])[CH:14]=2)=[CH:24][CH:23]=1
Reactant: CCCc1cc(Oc2ccc(Cl)cc2)ccc1C(O)c1cc(OC)c(Cl)c([Si](C)(C)C)c1F
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1cc(Oc2ccc(Cl)cc2)ccc1C(=O)c1cc(OC)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of the product from Step 2 (1.9 g, 3.7 mmol), N-methylmorpholine-N-oxide (0.70 g, 6.0 mmol), tetrapropylammonium perruthenate (70 mg, 0.2 mmol) and 4 Å molecular sieves (2.0 g) in dichloromethane (20 mL) was stirred at 25° C. for 1 h. The reaction mixture was diluted with diethyl ether (60 mL) and filtered through a short path of silica gel. Removal of the solvent gave the crude product. The crude product was dissolved in THF (20 mL) and treated with tetrabutylammonium fluoride (1M in THF, 5.6 mL, 5.6 mmol) for 10 min. The reaction mixture was diluted with ethyl acetate, washed with brine, dried and concentrated. The residue was purified by chromatography on silica gel to give the title product.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[C@H:15]([OH:24])[CH2:16][C@H:17]([OH:23])[CH2:18][C:19]([O:21]C)=[O:20])=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:3].[OH-].[Na+:33].CC(C)=O>O.CO>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:24])[CH2:16][CH:17]([OH:23])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:33]
Reactant: COC(=O)C[C@@H](O)C[C@@H](O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(C)=O
Solvent: O
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 65 °C
Reaction time: 3.5 h
Yield: 8.2 %

Procedure:
Fluvastatin methyl ester (3.0 g) was added to a solution of NaOH (1 eq.) in water (0.75 ml) and methanol (7.5 ml). The mixture was stirred at about 65° C. for 3.5 h. Then, another portion of NaOH (0.5 eq.) in water (0.4 ml) was added. After another 40 min the starting material was no longer detectable by HPLC. Acetone (58 ml) was dripped into the solution over 25 min. Turbidity appeared in the solution. The mixture was cooled slowly to room temperature and stirred overnight. The product was isolated by filtration under nitrogen, washed with acetone (20 ml) and dried at 50° C. in a vacuum oven for 24 h to obtain 0.25 g (8.2%) of fluvastatin sodium Form XXX.
Reaction SMILES: C([Al]([CH2:6][CH3:7])CC)C.CNCCNC.C[O:15][C:16](=O)[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[N:19][C:18]=1[O:25][CH3:26].Cl>C1(C)C=CC=CC=1.CCCCCC>[CH3:26][O:25][C:18]1[C:17]([C:16](=[O:15])[CH2:6][CH3:7])=[CH:22][CH:21]=[C:20]([O:23][CH3:24])[N:19]=1
Reactant: CC[Al](CC)CC
Reactant: COC(=O)c1ccc(OC)nc1OC
Agent: CNCCNC
Agent: Cl
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCC(=O)c1ccc(OC)nc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under nitrogen atmosphere, 15% hexane solution of triethyl aluminium was dropped at 0° C. to 26 m solution of toluene with 0.6 ml of N,N′-dimethyl-ethan-1,2-diamine, and the mixture was stirred at room temperature for 1 hour. Then, 5 ml solution of toluene with 1 g of 2,6-dimethoxy-nicotinic acid methylester was dropped at room temperature, and the mixture was stirred at 130° C. for 1 hour. The reaction solution was cooled down under ice temperature, 1M of hydrochloric acid was added, and extracted with ethyl acetate. Ethyl acetate layer was washed with saturated saline solution, dried with anhydrous sodium sulfate. The solvents were distilled outunder reduced pressure to obtain 156 mg of the above compound.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[C:5]2[N:6]=[C:7]([NH:16][NH2:17])[CH:8]=[C:9]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[N:4]2[N:3]=1.C(O)(=O)C.[CH3:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O>C(O)C>[CH3:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=[N:17][NH:16][C:7]1[CH:8]=[C:9]([N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)[N:4]2[N:3]=[C:2]([CH3:1])[CH:18]=[C:5]2[N:6]=1
Reactant: Cc1cccc(C=O)c1
Reactant: Cc1cc2nc(NN)cc(N3CCOCC3)n2n1
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cccc(C=NNc2cc(N3CCOCC3)n3nc(C)cc3n2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
There was dissolved, in ethanol (2 mL), (2-methyl-7-morpholin-4-yl-pyrazolo-[1,5-a]pyrimidin-5-yl)-hydrazine (24.7 mg, 0.0995 mM), then acetic acid (5.0 μL, 0.087 mM) and 3-methyl-benzaldehyde (12.9 μL, 0.109 mM) were added to the solution and the resulting mixture was stirred at room temperature for 2 hours. This reaction liquid was filtered and the resulting solid was washed with methanol to thus give the title compound (29.6 mg, yield: 85%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[NH:13][C:12]1=[O:23])(=[O:10])=[O:9].[CH3:24][S:25](Cl)(=[O:27])=[O:26].O>N1C=CC=CC=1>[Cl:22][C:16]1[CH:15]=[C:14]2[C:19]([C:20](=[O:21])[N:11]([S:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH:1][S:25]([CH3:24])(=[O:27])=[O:26])(=[O:10])=[O:9])[C:12](=[O:23])[NH:13]2)=[CH:18][CH:17]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccccc1S(=O)(=O)n1c(=O)[nH]c2cc(Cl)ccc2c1=O
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)Nc1ccccc1S(=O)(=O)n1c(=O)[nH]c2cc(Cl)ccc2c1=O
Yield: 66.7 %

Procedure:
22 mg (0.06 mmol) of Compound 2 was dissolved in 200 μl of pyridine, 11.6 μl (0.15 mmol) of methanesulfonyl chloride was added dropwise, then the resultant mixture was stirred at room temperature overnight. An excess amount of water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N aqueous hydrochloric acid solution and saturated saline, then dried over anhydrous magnesium sulfate and concentrated to obtain a crude product. The crude product was crystallized from diethyl ether to obtain 16 mg (0.04 mmol) of the above-identified compound. Properties: colorless crystal, Melting point: >200° C. (decomposition), PMR (δ ppm, DMSO-d6): 3.61 (3H, s), 7.10 (1H, d), 7.20 (1H, d), 7.74 (1H, d), 7.82-7.90 (4H, m), 8.34 (1H, d), 11.70 (1H, s).
Reaction SMILES: [F:1][CH:2]([F:13])[CH2:3][CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][CH:9](Br)[CH2:8][CH2:7]1.Cl[SiH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1.Cl[SiH]1CCC(C2C=CC(F)=C(F)C=2)CC1>>[F:1][CH:2]([F:13])[CH2:3][CH2:4][CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([Si@H:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=3)[CH2:17][CH2:16]2)[CH2:8][CH2:7]1
Reactant: FC(F)CCCC1CCC(Br)CC1
Reactant: Clc1ccc(C2CC[SiH](Cl)CC2)cc1
Agent: Fc1ccc(C2CC[SiH](Cl)CC2)cc1F
Product: FC(F)CCC[C@H]1CC[C@H]([Si@H]2CC[C@H](c3ccc(Cl)cc3)CC2)CC1

Procedure:
The above compound was obtained in the same manner as Example 6, using 4-(4,4-difluorobutyl)cyclohexylbromide and 4-(4-chloro-4-silacyclohexyl)-1-chlorobenzene instead of 4-(4-fluorobutyl)cyclohexybromide and 4-(4-chloro-4-silacyclohexyl)-1,2-difluorobenzene, respectively.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH2:6][CH2:5][C:4]1=[O:54])[CH3:2].B(F)(F)F.[CH3:59][CH2:60]OCC.[N+](=CC)=[N-]>CCOCC>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH2:59][CH3:60])[CH2:45]2)[CH:7]([CH3:53])[CH2:6][CH2:5][C:4]1=[O:54])[CH3:2]
Reactant: CCOCC
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)CCC1=O)C(C)CC2OC
Agent: CC=[N+]=[N-]
Agent: FB(F)F
Product: CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-di-methoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (200 mg, Example 38) in ether (6 ml) is added borontrifluoride etherate (10 μl) followed by freshly prepared diazoethane (100 fold excess). The mixture is stirred at room temperature for 15 min and quenched with sat'd aqueous sodium bicarbonate solution. The organic layer is separated, washed (sat'd aqueous NaCl) and dried over anhydrous magnesium sulfate. Removal of solvent followed by preparative tlc on silica to separate the regioisomers gives the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[CH3:34][NH2:35]>C1COCC1.CCOC(C)=O>[CH3:34][NH:35][S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:10]2[N:9]=[C:8]([C:6]3[CH:5]=[C:4]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][CH:25]=4)[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:13]=[CH:12][CH:11]=2)[CH:15]=1)(=[O:22])=[O:21]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Reactant: CN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1cccc(-c2cccc(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C)n3)n2)c1
Yield: 65.7 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.200 g, 0.409 mmol) by treatment with commercially available methylamine (2 M in THF, 2.05 ml, 4.1 mmol) in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.130 g, 65%) as a white solid. MS (ISP) 484.2 [(M+H)+]; mp 176° C.
Reaction SMILES: [O-]CC.[Na+].[OH:5][C:6](=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1)[C:7]([OH:9])=[O:8].[BH4-].[Na+].O>CO.CCCCCCC.C(OCC)(=O)C>[OH:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)C(O)=Cc1cccc([N+](=O)[O-])c1
Agent: CC[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: O=C(O)C(O)Cc1cccc([N+](=O)[O-])c1
Temperature: 7.5 °C
Reaction time: 0.5 h
Yield: 56.8 %

Procedure:
Sodium ethoxide (1.8 g, 26.4 mmol) was added portionwise at 0° C. to a stirred solution of 2-hydroxy-3-(3-nitrophenyl)acrylic acid (5.25 g, 25.0 mmol) in methanol (131 ml) to form a clear, pale yellow solution. Sodium borohydride (1 g, 26.4 mmol) was then carefully added in two portions and the mixture stirred at 5-10° C. for 30 mins. A small amount of water was then added to quench the reaction and destroy any excess NaBH4. The methanol was removed in vacuo to give a solid residue, which was ground with a 5:2 mixture of ethyl acetate and heptane (21 ml) then further ground with 3% aqueous methanol. The resulting solid was collected by filtration and dried in vacuo to give 2-hydroxy-3-(3-nitrophenyl)propionic acid (3.0 g, 57%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH:21][C:22](=[O:38])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]2[CH:36]=[CH:35][N:34]=[C:33]2[CH3:37])[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([N:32]5[CH:36]=[CH:35][N:34]=[C:33]5[CH3:37])[CH:27]=4)[CH2:23][C:22](=[O:38])[NH:21][C:9]=3[CH:10]=2)=[CH:19][CH:18]=1
Reactant: Cc1nccn1-c1cccc(C(=O)CC(=O)Nc2cc(-c3ccc(F)cc3)ccc2NC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nccn1-c1cccc(C2=Nc3ccc(-c4ccc(F)cc4)cc3NC(=O)C2)c1

Procedure:
Prepared from (4′-fluoro-3-{3-[3-(2-methyl-imidazol-1-yl)-phenyl]-3-oxo-propionylamino}-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example K53) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (178 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][C:19]=1[N+:20]([O-])=O)[CH2:16][C@:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]1=[O:15])[CH2:5]2.CCOC(C)=O>CO.[Pd]>[NH2:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][C:19]=1[NH2:20])[CH2:16][C:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]1=[O:15])[CH2:5]2
Reactant: Nc1cc2c(cc1[N+](=O)[O-])C[C@]1(C2)C(=O)Nc2ncccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1cc2c(cc1N)CC1(C2)C(=O)Nc2ncccc21
Reaction time: 18 h

Procedure:
A mixture of 10% Pd/C (900 mg) and (S)-5-amino-6-nitro-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one from Step A (3.00 g, 10.1 mmol) was stirred vigorously in MeOH (500 mL) and EtOAc (700 mL) under an atmosphere of hydrogen (ca. 1 atm). After 18 h, the mixture was filtered through a pad of Celite, washing with MeOH, and the filtrate was concentrated in vacuo to give the title compound. MS: m/z=267 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:8][CH:9]=[N:10][N:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:28][C:29]1[C:30]([F:40])=[CH:31][C:32]([F:39])=[C:33]([S:35](Cl)(=[O:37])=[O:36])[CH:34]=1.O>C1COCC1>[Cl:28][C:29]1[C:30]([F:40])=[CH:31][C:32]([F:39])=[C:33]([S:35]([N:6]([CH2:5][C:4]2[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:3]=2[O:2][CH3:1])[C:7]2[S:8][CH:9]=[N:10][N:11]=2)(=[O:37])=[O:36])[CH:34]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)c(F)cc1F
Reactant: COc1ccc(CNc2nncs2)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57.8 %

Procedure:
To a solution of N-(2,4-dimethoxybenzyl)-1,3,4-thiadiazol-2-amine (WO 2010/079443; 5.00 g, 19.9 mmol) in THF (60 mL), lithium bis(trimethylsilyl)amide (1.0 M solution in THF; 24.0 mL, 24.0 mmol) was added at −78° C. The reaction solution was stirred at room temperature for 10 minutes, and a solution of 5-chloro-2,4-difluorobenzenesulfonyl chloride (5.41 g, 21.9 mmol) in THF (15 mL) was then added thereto at −78° C. The reaction solution was stirred at room temperature for 2 hours, and water (100 mL) was then added to the reaction solution, followed by extraction with ethyl acetate (100 mL). The thus obtained organic layer was washed with saturated saline (100 mL) and dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography (hexane/ethyl acetate=9:1) to yield the title compound (5.31 g, 58%) as a colorless solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](O)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25])C=O.N1CCCCC1>>[CH3:27][O:26][C:22]1[CH:21]=[C:18]([CH:11]=[CH:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH:17]=[C:16]([O:15][CH3:14])[C:23]=1[O:24][CH3:25]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: COc1cc(C=O)cc(OC)c1OC
Solvent: C1CCNCC1
Product: COc1cc(C=Cc2ccc([N+](=O)[O-])cc2)cc(OC)c1OC
Yield: 41 %

Procedure:
The title compound was prepared from p-nitrophenylacetic acid (18.6 g, 0.10 mol), 3,4,5-trimethoxy-benzaldehyde (19.6 g, 0.10 mol) and piperidine (5 mL) using the procedure described in Example 1, Step A. This procedure yielded a solid, 13.0 g (0.041 mol, 41%) of the desired product. mp: 192-195° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Br:11][C:12]1[C:20]2[C:15](=[CH:16][N:17]=[C:18]([CH2:21][OH:22])[CH:19]=2)[O:14][CH:13]=1.CCN(CC)CC>C1COCC1.C(Cl)Cl>[Br:11][C:12]1[C:20]2[C:15](=[CH:16][N:17]=[C:18]([CH:21]=[O:22])[CH:19]=2)[O:14][CH:13]=1
Reactant: OCc1cc2c(Br)coc2cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=Cc1cc2c(Br)coc2cn1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 99.4 %

Procedure:
Oxalyl chloride (1.77 mL, 20.1 mmol) is combined with CH2Cl2 (60 mL) in a dried flask under nitrogen, cooled to −78° C., treated dropwise with DMSO (2.86 mL, 40.25 mmol) and stirred for 20 min. The cooled solution is treated drop-wise with a solution of (3-bromofuro[2,3-c]pyridin-5-yl)methanol (4.0 mg, 17.5 mmol) in THF (50 mL), stirred for 1 h, then treated drop-wise with Et3N (12.2 mL, 87.5 mmol). The mixture is stirred for 30 min at −78° C., then 30 min at 0° C. The mixture is washed with saturated NaHCO3 (120 mL) and the organics dried over K2CO3 and concentrated in vacuo to a dark yellow solid (3.91 g). The crude material is chromatographed over 150 g slurry-packed silica gel, eluting with 30% EtOAc/hexane. The appropriate fractions are combined and concentrated in vacuo to afford 3.93 g (99%) of 3-bromofuro[2,3-c]pyridine-5-carbaldehyde as a white solid. MS (EI) m/z: 225 (M+).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].Cl[C:25]1[N:30]2[N:31]=[C:32]([CH3:34])[N:33]=[C:29]2[N:28]=[C:27]([CH3:35])[CH:26]=1>>[CH3:34][C:32]1[N:33]=[C:29]2[N:28]=[C:27]([CH3:35])[CH:26]=[C:25]([NH:1][CH2:2][C@@H:3]3[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]3[C:10]([C:12]3[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=3[N:19]3[N:23]=[CH:22][CH:21]=[N:20]3)=[O:11])[N:30]2[N:31]=1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Cc1cc(Cl)n2nc(C)nc2n1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2cc(C)nc3nc(C)nn23)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 7-chloro-2,5-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine. ESI-MS (m/z): 460 [M+1]+.