Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH2:12]([O:14][C:15](=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[CH3:13].CCOCC>ClCCl>[CH2:12]([O:14][C:15](=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[O:21])[CH3:13]
Reactant: CCOC(=O)CCCCCO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)CCCCC=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.6 %

Procedure:
To a solution of pyridinium chlorochromate (2.0 g) in dichloromethane (15 ml) was added a solution of 6-hydroxyhexanoic acid ethyl ester (1.0 g) in dichloromethane (1.5 ml) in one portion and stirred for 1.5 hours at ambient temperature. Ether (15 ml) was added to the reaction mixture, and the insoluble material removed by filtration and discarded. The filtrate was purified by silica gel chromatography (diethyl ether) to give 6-oxohexanoic acid ethyl ester (884.6 mg), as a pale green oil.
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.OP([O-])(O)=O.[K+].OP([O-])([O-])=O.[K+].[K+].[O-]S([O-])(=O)=O.[Mg+2].[Cl-].[K+].[O:34]=[C:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH:36]1[C:41]([O:43][CH2:44][CH3:45])=[O:42].COC1C=CC(C=O)=CC=1>C(O)C>[OH:34][C@H:35]1[CH2:40][CH2:39][CH2:38][CH2:37][C@@H:36]1[C:41]([O:43][CH2:44][CH3:45])=[O:42]
Reactant: CCOC(=O)C1CCCCC1=O
Agent: COc1ccc(C=O)cc1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=P([O-])(O)O
Solvent: CCO
Product: CCOC(=O)[C@H]1CCCC[C@@H]1O
Reaction time: 48 h
Yield: 69.2 %

Procedure:
Geotrichum candidum (ATCC 34614) was cultured according to the method of Buisson and Azerad (Tet. Lett. 27, 2631-2634 (1986), herein incorporated by reference) in one liter of a medium of glucose (30 grams), KH2PO4 (1 gram), K2HPO4 (2 grams), corn steep liquor (10 grams) MgSO4.7H20 (0.5 gram), NaNO3 (2 grams), FeSO4.7H20 (0.02 gram), and KCl (0.5 gram) with rotary shaking at 25° C. Two grams of ethyl 2-oxocyclohexanecarboxylate was dissolved in 2 ml of 95% ethanol, the resulting solution was added to the culture, and shaking was resumed. The reaction was followed by TLC (staining with anisaldehyde) to monitor the consumption of starting material and the production of product alcohol. After approximately 48 hours the reaction was judged complete, and the reaction was terminated by removing from the shaker and adding 20-30 grams of Celite. The resulting suspension was suction filtered through a pad of Celite and the clear yellow filtrate was extracted with ethyl acetate (4×200 ml). The extracts were combined, dried over MgSO4, filtered, and rotary evaporated to leave 1.4 grams of (1S,2S)-ethyl 2-hydroxycyclohexanecarboxylate as a yellow oil. The chiral purity of the product was greater than 99% as judged by chiral chromatography.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[CH:10]=[C:6]2[N:5]=[C:4]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:3]=1.[H][H]>C(Cl)Cl.CO.C(N(CC)CC)C.[Pd]>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([C:9]2[CH:10]=[C:6]3[N:5]=[C:4]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:3]=[CH:2][N:7]3[N:8]=2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1cc(Cl)n2nc(-c3ccc(OC)cc3)cc2n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccn2nc(-c3ccc(OC)cc3)cc2n1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 70.6 %

Procedure:
To a solution of ethyl 7-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidine-5-carboxylate (767 mg; 2.31 mmol) in methylene chloride (10 mL), methanol (10 mL) and triethylamine (2 mL) was added 10% Pd on carbon (77 mg) and the mixture was cooled to 0° C. The reaction flask was put under vacuum and then hydrogen was introduced using a balloon. A second cycle of vacuum and hydrogen purge was performed and the mixture was stirred at 0° C. for 1.5 h. The mixture was flushed with two cycles of vacuum and nitrogen, diluted with methylene chloride and then filtered through a 0.45 micron filter to remove the catalyst. Concentration afforded the crude product which was triturated in methanol (25 mL) and filtered to afford 485 mg (71%) of the title compound. LCMS m/z 298.1 (M+H)+, ret. time=2.53 min.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]3[CH:18]=[N:19][CH:20]=[C:16]3[CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)=[O:5])C>C(O)C.[OH-].[Na+]>[C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:17]3[CH:18]=[N:19][CH:20]=[C:16]3[CH:15]=[CH:14][CH:13]=2)=[CH:10][CH:11]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1ccc(-c2cccc3cncn23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(-c2cccc3cncn23)cc1

Procedure:
A solution of 1.18 g or 5-(p-ethoxycarbonylphenyl)imidazo[1,5-a]pyridine in 10 ml of ethanol and 14 ml of 1N sodium hydroxide solution is refluxed for 3 h, cooled and evaporated. The residue is partitioned between water and ethyl acetate. The aqueous phase is separated and adjusted to pH 5. The solid is filtered, washed with water and dried to yield the title compound, m.p. 308°-310° (dec.).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:8]([CH3:12])=[CH:9][C:10]=1[NH2:11])[NH2:7])([O-:3])=[O:2].C(=O)([O-])[O-].[Ca+2].Cl[CH2:19][CH2:20][CH2:21][OH:22]>O>[N+:1]([C:4]1[CH:5]=[C:6]([C:8]([CH3:12])=[CH:9][C:10]=1[NH2:11])[NH:7][CH2:19][CH2:20][CH2:21][OH:22])([O-:3])=[O:2]
Reactant: OCCCCl
Reactant: Cc1cc(N)c([N+](=O)[O-])cc1N
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Product: Cc1cc(N)c([N+](=O)[O-])cc1NCCCO

Procedure:
16.7 g (0.1 mol) of 3-nitro-4-amino-6-methylaniline, 40 ml of water, 6.6 g (0.066 mol) of calcium carbonate and 12.42 g (0.132 mol) of 3-chloropropan-1-ol are heated on a boiling water-bath for 7 hours 30 minutes, whilst stirring.
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH:19]C(=O)C(O)(C)C)[CH:14]=2)[CH2:9][CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Cl>O1CCOCC1.O>[NH2:19][C:15]1[CH:14]=[C:13]([CH:10]2[CH2:11][CH2:12][N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:8][CH2:9]2)[CH:18]=[CH:17][CH:16]=1
Reactant: CCCCCCN1CCC(c2cccc(NC(=O)C(C)(C)O)c2)CC1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CCCCCCN1CCC(c2cccc(N)c2)CC1

Procedure:
A solution of N-hexyl-4-(3-(2-hydroxy-2-methylpropanoylamino)phenyl)piperidine (Example 158) in 1,4-dioxan:5N aqueous hydrochloric acid solution (1:1, 10 ml) was heated under reflux overnight. The reaction mixture was cooled, diluted with water (10 ml) and extracted with diethyl ether (3×10 ml). The pH of the aqueous layer was adjusted to 8-9 using 5N aqueous sodium hydroxide, and extracted with dichloromethane (5×10 ml). The combined extracts were washed with brine (10 ml), dried (Na2SO4) and concentrated in vacuo to give the title compound as an oil which was not purified further (178 mg, 61% over two steps).
Reaction SMILES: Cl.[CH2:2]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[N:15]=[CH:16][N:17]3[CH:21]=[CH:20][S:19][C:18]=23)[CH2:11][C@@H:10]([O:22][Si](C(C)(C)C)(C)C)[CH2:9]1)=[O:7])[CH:3]=[CH2:4].C(=O)([O-])O.[Na+]>C(#N)C.C(OCC)(=O)C>[CH2:2]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[N:15]=[CH:16][N:17]3[CH:21]=[CH:20][S:19][C:18]=23)[CH2:11][C@@H:10]([OH:22])[CH2:9]1)=[O:7])[CH:3]=[CH2:4]
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1Cc1ncn2ccsc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1Cc1ncn2ccsc12
Reaction time: 0.33 h
Yield: 107.9 %

Procedure:
Concentrated hydrochloric acid (0.204 ml) is added dropwise to a solution of 206 mg of (3R,5R)-1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5-(imidazo[5,1-b]thiazol-7-yl)methylpyrrolidine in 5 ml of dry acetonitrile under ice cooling, and the mixture is stirred at that temperature for 20 min. The reaction solution is diluted with 20 ml of ethyl acetate, saline is added to the diluted solution, the mixture is adjusted to pH 9 by addition of a saturated aqueous sodium hydrogencarbonate solution, and the mixture is extracted three times with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate and filtered, and the solvent is removed by evaporation under reduced pressure. The residue is purified by column chromatography on silica gel (chloroform:methanol=10:1) to give 162 mg of (3R,5R)-1-allyloxycarbonyl-3-hydroxy-5-(imidazo[5,1-b]thiazol-7-yl)methylpyrrolidine.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]([CH:10]=1)=[N:7][O:8][N:9]=2.C(=O)([O-])[O-].[Na+].[Na+].[CH3:17][N:18]([CH3:28])[C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>COCCOC.O>[N:9]1[O:8][N:7]=[C:6]2[CH:10]=[C:2]([C:22]3[CH:23]=[CH:24][C:19]([N:18]([CH3:28])[CH3:17])=[CH:20][CH:21]=3)[CH:3]=[CH:4][C:5]=12
Reactant: CN(C)c1ccc(B(O)O)cc1
Reactant: Brc1ccc2nonc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CN(C)c1ccc(-c2ccc3nonc3c2)cc1
Temperature: 25 °C

Procedure:
500 mg (2.5 mmol) 5-bromo-benzo[1,2,5]oxadiazole and 313 mg (0.1 eq.) tetrakis-(triphenylphosphine)palladium are stirred for 30 minutes at room temperature in 10 mL 1,2-dimethoxyethane. 533 mg (2 eq.) sodium carbonate are dissolved in 1.8 mL water and added to the reaction mixture, followed by 663 mg (1.6 eq.) 4-(dimethylamino)phenylboronic acid. After stirring at reflux for 18 h, the reaction mixture is cooled to room temperature and extracted with ethyl acetate and water. The organic phases are combined, dried with magnesium sulfate, filtered and evaporated. The residue is column chromatographed (hexane, then hexane/ethyl acetate 8:1 then 5:1) to yield the desired product as a yellow solid. MS(ES+): 240 (M+1).
Reaction SMILES: Cl.[C:2]1([C:8]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@@H:16]3[C@@H:12]([CH2:13][NH:14][CH2:15]3)[C@@:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])([OH:17])[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]([O:36][C:37]([NH:39][C@@H:40]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:41](O)=[O:42])=[O:38])([CH3:35])([CH3:34])[CH3:33]>>[C:26]1([C:8]2([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C@@H:16]3[C@@H:12]([CH2:13][N:14]([C:41](=[O:42])[C@@H:40]([NH:39][C:37]([O:36][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:38])[C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[CH2:15]3)[C@@:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])([OH:17])[CH2:10][CH2:9]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)c1ccccc1
Reactant: COc1ccccc1[C@]1(O)CCC(c2ccccc2)(c2ccccc2)[C@H]2CNC[C@H]21
Agent: Cl
Product: COc1ccccc1[C@]1(O)CCC(c2ccccc2)(c2ccccc2)[C@H]2CN(C(=O)[C@@H](NC(=O)OC(C)(C)C)c3ccccc3)C[C@H]21
Yield: 11.1 %

Procedure:
By working in accordance with Example 4, starting from 2.25 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)perhydroisoindol-4-ol hydrochloride and 1.25 g of (S)-2-tert-butoxycarbonylamino-2-phenylacetic acid, 0.35 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[(S)-2-tert-butoxycarbonylamino-2-phenylacetyl]perhydroisoindol-4-ol is obtained in the form of a white foam.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:14]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.C1(S(Cl)(=O)=O)C=CC=CC=1.[OH-].[NH4+:49]>>[CH3:1][C:2]1[N:3]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[C:6]([NH2:49])[C:5]=2[N:14]=1
Reactant: [NH4+]
Reactant: Cc1nc2cnc3ccccc3c2n1CCCCC(=O)N1CCOCC1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S(=O)(Cl)c1ccccc1
Agent: [OH-]
Product: Cc1nc2c(N)nc3ccccc3c2n1CCCCC(=O)N1CCOCC1

Procedure:
2-Methyl-1-(5-morpholin-4-yl-5-oxopentyl)-1H-imidazo[4,5-c]quinoline (8.4 g, 24 mmol) was treated with mCPBA (7.19 g, 41.7 mmol), ammonium hydroxide (40 mL), and benzenesulfonyl chloride (5.93 mL, 46.5 mmol) according to the method described in Part D of Example 36. The crude product was purified by column chromatography on silica gel (eluting with 90:10 dichloromethane:methanol). The resulting product was triturated with 10% aqueous sodium hydroxide, isolated by filtration, washed with water, and dried overnight in a vacuum oven to provide 0.487 g of 2-methyl-1-(5-morpholin-4-yl-5-oxopentyl)-1H-imidazo[4,5-c]quinolin-4-amine as an off-white powder, mp 218-219° C.
Reaction SMILES: [O:1]1[CH2:5][CH:4]=[C:3]([C:6]2[CH:11]=[C:10]([CH3:12])[C:9]([C:13]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]4[C:14]=3[CH2:15][CH2:16][C@H:17]4[O:23][C:24]3[CH:37]=[CH:36][C:27]4[C@H:28]([CH2:31][C:32]([O:34]C)=[O:33])[CH2:29][O:30][C:26]=4[CH:25]=3)=[C:8]([CH3:38])[CH:7]=2)[CH2:2]1.[OH-].[Na+]>O>[O:1]1[CH2:5][CH:4]=[C:3]([C:6]2[CH:7]=[C:8]([CH3:38])[C:9]([C:13]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]4[C:14]=3[CH2:15][CH2:16][C@H:17]4[O:23][C:24]3[CH:37]=[CH:36][C:27]4[C@H:28]([CH2:31][C:32]([OH:34])=[O:33])[CH2:29][O:30][C:26]=4[CH:25]=3)=[C:10]([CH3:12])[CH:11]=2)[CH2:2]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(C6=CCOC6)cc5C)ccc(F)c43)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(C2=CCOC2)cc(C)c1-c1ccc(F)c2c1CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)O

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-4-(4-(2,5-dihydrofuran-3-yl)-2,6-dimethylphenyl)-7-fluoro-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate following a procedure analogous to that described in Step 2 of Intermediate 30 using NaOH instead of LiOH×H2O. LC (method 9): tR=0.16 min; Mass spectrum (ESI+): m/z=501 [M+H]+.
Reaction SMILES: CS([C:5]1[N:9]=[C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[CH3:16])[S:7][N:6]=1)(=O)=O.[CH2:17]([OH:21])[C:18]#[C:19][CH3:20].[H-].[Na+]>CN(C)C=O.[Cl-].[Na+].O>[CH3:16][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH:10]1[C:8]1[S:7][N:6]=[C:5]([O:21][CH2:17][C:18]#[C:19][CH3:20])[N:9]=1
Reactant: CC#CCO
Reactant: CC1CCCCC1c1nc(S(C)(=O)=O)ns1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCOc1nsc(C2CCCCC2C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.4 %

Procedure:
160 mg of 3-methylsulfonyl-5-(2-methylcyclohexyl)-1,2,4-thiadiazole and 52 mg of 2-butyn-1-ol were dissolved in 1.5 ml of N,N-dimethylformamide, 32 mg of sodium hydride (60% in oil) was added thereto under ice-cooling, and the reaction mixture was stirred for 1 hour under ice-cooling and for 12 hours at room temperature. Then, the reaction mixture was added to saturated brine, and extracted with t-butyl methyl ether. The organic layer was concentrated under reduced pressure, and the residue obtained was subjected to silica gel column chromatography to give 39 mg of 5-(2-methylcyclohexyl)-3-(2-butynyloxy)-1,2,4-thiadiazole (hereinafter referred to as the present invention compound (10)).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=3)[O:11][C:10](=[O:22])[CH:9]=2)[CH2:3][CH2:2]1.[CH:23]1[C:28]([CH:29]=O)=[CH:27][C:26]2[O:31][CH2:32][O:33][C:25]=2[CH:24]=1>>[O:33]1[C:25]2[CH:24]=[CH:23][C:28]([CH2:29][N:1]3[CH2:2][CH2:3][CH:4]([NH:7][C:8]4[C:17]5[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:20])([F:19])[F:21])[CH:16]=5)[O:11][C:10](=[O:22])[CH:9]=4)[CH2:5][CH2:6]3)=[CH:27][C:26]=2[O:31][CH2:32]1
Reactant: O=c1cc(NC2CCNCC2)c2cc(C(F)(F)F)ccc2o1
Reactant: O=Cc1ccc2c(c1)OCO2
Product: O=c1cc(NC2CCN(Cc3ccc4c(c3)OCO4)CC2)c2cc(C(F)(F)F)ccc2o1
Yield: 43.8 %

Procedure:
4-(1-Benzo[1,3]dioxol-5-ylmethyl-piperidin-4-ylamino)-6-trifluoromethyl-chromen-2-one was prepared according to a reductive amination procedure using 4-(piperdin-4-ylamino)-6-trifluoromethyl-chromen-2-one (116 mg, 0.373 mmol) and piperonal (62 mg, 0.411 mmol) to provide the title product as a white solid (73 mg, 44%). MS (APCI) m/z 447 [M+H]+, 445 [M−H]+, 481 [M+Cl]+; 1H NMR (300 MHz, DMSO-D6) δ ppm 1.64 (m, 2H) 1.92 (m, J=9.83 Hz, 2H) 2.09 (m, 2H) 2.84 (m, J=11.53 Hz, 2H) 3.51 (m, 1H) 5.34 (s, 1H) 5.99 (s, 2H) 6.76 (d, J=6.44 Hz, 1H) 6.85 (d, J=8.82 Hz, 2H) 7.51 (t, J=9.32 Hz, 2H) 7.92 (dd, J=8.82, 1.70 Hz, 1H) 8.63 (s, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6](=[O:18])[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[C:9]([N+:15]([O-])=O)[CH:8]=1.[H][H]>[Pd].C(OCC)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6](=[O:18])[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[C:9]([NH2:15])[CH:8]=1
Reactant: COCCNC(=O)c1ccc(SC)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCCNC(=O)c1ccc(SC)c(N)c1
Yield: 94.9 %

Procedure:
A suspension of N-(2-methoxyethyl)-4-methylthio-3-nitrobenzamide (1.6 g) and palladium on charcoal (1.1 g; 5%) in ethyl acetate (60 ml) was shaken under an atmosphere of hydrogen at atmospheric pressure until hydrogen uptake ceased. The mixture was filtered and the residue was rinsed with ethyl acetate. The filtrate was concentrated in vacuo to leave N-(2-methoxyethyl)-4-methylthio-3-aminobenzamide (1.35 g) in the form of an oil that crystallised on standing, m.p. 66°-68° C. [Elemental analysis: C,54.8; H,6.69; N,11.5; S,12.9%; calculated: C,54.98; H,6.71; N,11.66; S,13.34%].
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][C@H:14]([CH3:16])[O:13][C@H:12]([CH3:17])[CH2:11]2)[CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[C:20](B(O)O)=[CH:21][C:22]([F:25])=[N:23][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[Cl:18][C:19]1[C:20]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([NH:8][CH2:9][CH:10]3[CH2:15][C@H:14]([CH3:16])[O:13][C@H:12]([CH3:17])[CH2:11]3)[N:7]=2)=[CH:21][C:22]([F:25])=[N:23][CH:24]=1
Reactant: C[C@@H]1CC(CNc2cccc(Br)n2)C[C@H](C)O1
Reactant: OB(O)c1cc(F)ncc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: C[C@@H]1CC(CNc2cccc(-c3cc(F)ncc3Cl)n2)C[C@H](C)O1
Temperature: 95 °C

Procedure:
A mixture of 6-bromo-N-(((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine (110 mg, 0.36 mmol), 5-chloro-2-fluoro-pyridine-4-boronic acid (193 mg, 1.10 mmol), 0.55 ml 2.0M saturated sodium carbonate aqueous solution in 2 ml DME was purged with Argon for 3 min, PdCl2(dppf)CH2Cl2 (30 mg, 0.037 mmol) was added to this purged. The resulting mixture was heated at about 95° C. in an oil bath for 3.5 hours. Formation of the desired product was confirmed by LCMS: MH+ 350, 0.70 min. The preceding reaction mixture was diluted with ethyl acetate, washed with water, brine, dried over sodium sulfate and concentrated. The resulting residue was purified by ISCO eluting with 10% ethyl acetate in heptane to give 90 mg desired product as colorless oil. LCMS (m/z): 350 (MH+), retention time=0.70 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:20]2[CH:21]=[CH:22][O:23][C:19]=2[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[O:23][CH:22]=[CH:21][C:20]=4[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2occc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2ccoc2CCN1C(=O)c1cc2ncc(Br)cn2n1
Yield: 39 %

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 4-Methyl-4,5,6,7-tetrahydro-furo[3,2-c]pyridine to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:6]([Cl:23])[C:7]=1[CH2:8][CH:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16][CH2:15]2)[C:10]1=[O:22].[N:32]1[CH:37]=[CH:36][CH:35]=[C:34](B(O)O)[CH:33]=1.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.C([O-])(O)=O.[Na+].CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:34]2[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=2)[CH:5]=[C:6]([Cl:23])[C:7]=1[CH2:8][CH:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][C:17]([F:20])([F:21])[CH2:16][CH2:15]2)[C:10]1=[O:22]
Reactant: OB(O)c1cccnc1
Reactant: O=C1C(Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)CCN1C1CCC(F)(F)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: O=C1C(Cc2c(Cl)cc(-c3cccnc3)cc2Cl)CCN1C1CCC(F)(F)CC1
Temperature: 25 °C

Procedure:
Heat a solution of trifluoro-methanesulfonic acid 3,5-dichloro-4-[1-(4,4-difluoro-cyclohexyl)-2-oxo-pyrrolidin-3-ylmethyl]-phenyl ester (Preparation 33) (0.585 g, 1.15 mmol), pyridine-3-boronic acid (0.283 g, 2.30 mmol), Pd(PPh3)4 (133 mg), 11.5 mL of 0.1 M Na2CO3 aq solution in 11.5 mL of dimethoxy ethane at 80° C. for 24 hr. Cool the mixture to room temp and dilute with 20 mL of 1N NaHCO3. Dilute the mixture with 20 mL of EtOAc. Wash the organic layer with water, then brine, and dry over Na2SO4, filter and concentrate. Purify the crude material by chromatography to afford the title compound: mass spectrum (m/z): 439 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[C:7]([C:8]2[NH:9][C:10]3[C:15]([C:16]=2[C:17](=O)[CH2:18][CH2:19][C:20]([N:22]([CH3:24])[CH3:23])=O)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:6]([CH3:26])[O:5][N:4]=1)[CH3:2]>C1COCC1>[CH2:1]([C:3]1[C:7]([C:8]2[NH:9][C:10]3[C:15]([C:16]=2[CH2:17][CH2:18][CH2:19][CH2:20][N:22]([CH3:23])[CH3:24])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:6]([CH3:26])[O:5][N:4]=1)[CH3:2]
Reactant: CCc1noc(C)c1-c1[nH]c2ccccc2c1C(=O)CCC(=O)N(C)C
Solvent: C1CCOC1
Product: CCc1noc(C)c1-c1[nH]c2ccccc2c1CCCCN(C)C

Procedure:
A solution of 5.3 grams (0.015 mole) of 2-(3-ethyl-5-methyl-4-isoxazolyl)-N,N-dimethyl-γ-oxo-indole-3-butanamide in 75 ml dry THF is added dropwise to a refluxing suspension of 1.71 grams (0.045 mole) of LiAlH and 50 ml THF. The mixture is refluxed 2 hours after addition and then cooled and quenched by the addition of ethyl acetate, 2N sodium hydroxide and water. The mixture is filtered and the THF evaporated. The residue is dissolved in CH2Cl2, washed with water, dried over MgSO4, filtered and evaporated. The residue is dissolved in ether and converted to the hydrochloride salt with gaseous HCl giving the title compound as the hydrochloride, m.p. 155.5°-157.5° C.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([C:14]2[N:15]=[C:16]([NH:31][CH2:32][CH2:33][NH:34][C:35](=[O:37])[CH3:36])[C:17]3[CH:22]=[C:21]([CH2:23][O:24][CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[NH:20][C:18]=3[N:19]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CCN(CC)CC.C(Cl)Cl.[C:48]([C:50]1[CH:55]=[CH:54][C:53]([S:56](Cl)(=[O:58])=[O:57])=[CH:52][CH:51]=1)#[N:49]>C1COCC1>[C:48]([C:50]1[CH:51]=[CH:52][C:53]([S:56]([CH:23]([O:24][CH:25]2[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]2)[C:21]2[NH:20][C:18]3[N:19]=[C:14]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[N:15]=[C:16]([NH:31][CH2:32][CH2:33][NH:34][C:35](=[O:37])[CH3:36])[C:17]=3[CH:22]=2)(=[O:58])=[O:57])=[CH:54][CH:55]=1)#[N:49]
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)NCCNc1nc(-c2ccccc2)nc2[nH]c(COC3CCNCC3)cc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)NCCNc1nc(-c2ccccc2)nc2[nH]c(C(OC3CCNCC3)S(=O)(=O)c3ccc(C#N)cc3)cc12
Reaction time: 2 h
Yield: 23.5 %

Procedure:
Amine 14 (62 mg) and NEt3 (0.1 mL) were stirred in THF (6 mL) and DCM (6 mL) and cooled to 5° C. 4-Cyanophenylsulfonyl chloride (30 mg) was added dropwise by syringe, and stirring was continued at rt for 2 h, then the reaction mixture was concentrated. The residue was redissolved in DCM and washed with saturated NaHCO3, brine, and dried over MgSO4. After removal of solvent, the crude product was purified by preparative TLC (silica gel, DCM/MeOH=12/1) to give 16 mg (36%) of 15.3 as an off-white foam. 1H-NMR (200 MHz, CDCl3): δ 1.50-1.67 (m, 2H), 1.80 (s, 3H), 2.94-3.20 (m, 4H), 3.32-3.46 (m, 1H), 3.50-3.70 (m, 2H), 3.80-3.95 (m, 2H), 4.47 (s, 2H), 5.72 (brs, 1H), 6.22 (s, 1H), 6.81 (brs, 1H), 7.20-7.38 (m, 3H), 7.75-7.90 (m, 4H), 8.37-8.40 (m, 2H), 9.37 (brs, 1H); MS (ES): 574.1 [MH+].