Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17](B3OC(C)(C)C(C)(C)O3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.Br[C:29]1[C:33]2[CH:34]=[N:35][C:36]([NH2:50])=[C:37]([O:38][CH:39]([C:41]3[C:46]([Cl:47])=[CH:45][CH:44]=[C:43]([F:48])[C:42]=3[Cl:49])[CH3:40])[C:32]=2[O:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.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:49][C:42]1[C:43]([F:48])=[CH:44][CH:45]=[C:46]([Cl:47])[C:41]=1[CH:39]([O:38][C:37]1[C:32]2[O:31][CH:30]=[C:29]([C:17]3[CH:16]=[N:15][N:14]([CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH:18]=3)[C:33]=2[CH:34]=[N:35][C:36]=1[NH2:50])[CH3:40].[ClH:47]
Reactant: CC(Oc1c(N)ncc2c(Br)coc12)c1c(Cl)ccc(F)c1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)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: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(Oc1c(N)ncc2c(-c3cnn(C4CCNCC4)c3)coc12)c1c(Cl)ccc(F)c1Cl
Product: Cl
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
To a stirred mixture of 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (26.94 mg, 0.071 mmol), 3-bromo-7-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]furo[3,2-c]pyridin-6-ylamine (20.0 mg, 0.047 mmol), potassium carbonate (19.7 mg, 0.14 mmol) in DME (2.0 mL) and H2O (0.40 mL) was added Pd(PPh3)4 (2.8 mg, 0.0024 mmol) under Nitrogen. The resulting mixture was refluxed at 100° C. for 30 min. LC-MS indicated completion of reaction. The solvent was then removed under reduced pressure and the resulting residue was purified by a flash chromatography (2% MeOH in DCM). MS (ES+): m/z 590.07, 592.08 (MH+). HPLC: tR=3.48 min (ZQ3, polar—5 min). The product purified above was then dissolved in 2 mL dioxane, to this solution was added solution of 4 N HCl in dioxane (1 mL) at r.t., the resulting mixture was stirred at r.t. for 1.5 h. LC-MS indicated completion of reaction. The solvent was removed under reduced pressure to give the title compound as HCl salt. The 1H NMR spectrum matches that of Example 5.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:27][CH3:28])[C:13]([N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][C@H:16]1[C:24]([OH:26])=O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[F:30][C:31]([F:35])([F:34])[CH2:32][NH2:33].C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl>[F:30][C:31]([F:35])([F:34])[CH2:32][NH:33][C:24]([C@@H:16]1[CH2:17][C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:15]1[C:13](=[O:14])[C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:27][CH3:28])=[O:26]
Reactant: NCC(F)(F)F
Reactant: CC[C@H](NC(=O)OCc1ccccc1)C(=O)N1c2ccccc2C[C@H]1C(=O)O
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H](NC(=O)OCc1ccccc1)C(=O)N1c2ccccc2C[C@H]1C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1-(N-Benzyloxycarbonyl-2(S)-aminobutyryl)-indoline-2(S)-carboxylic acid (0.382 g, 1 mmol) and 2,2,2-trifluoroethylamine hydrochloride (0.207 g, 1.5 mmol) were dissolved in dried dichloromethane (10 ml), and triethylamine (5.5 mmol) was added, followed by bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.508 g, 2.0 mmol) under nitrogen at 0° C. The temperature was allowed to rise to room temperature and the mixture was stirred at room temperature for 24 hours, then filtered. The filtrate was concentrated under reduced pressure to give a brown solid which was purified by column chromatography on silica gel using 7:3 petroleum spirit: ethyl acetate as eluent to afford a white solid.
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[C:14]1[O:15][C:16]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-])=O)[C:17]=2[N:18]=1.O>Cl>[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[C:14]1[O:15][C:16]2[C:17](=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=2)[N:18]=1
Reactant: O=[N+]([O-])c1cccc2oc(-c3c(F)cccc3F)nc12
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Product: Nc1cccc2oc(-c3c(F)cccc3F)nc12
Temperature: 60 °C
Reaction time: 2 h

Procedure:
14.3 g (63.5 mmol; 5 eq.) of tin chloride is added to a solution of 3.5 g (12.7 mmol) of 2-(2,6-difluorophenyl)-4-nitro-1,3-benzoxazole in 60 ml of concentrated hydrochloric acid. The mixture is stirred for 2 hours at 60° C., then, after returning to ambient temperature and the addition of 100 ml of water, is neutralized by a 50% aqueous solution of soda. The precipitate formed is filtered on a Celite bed and washed with ethanol. The resulting solution is concentrated under reduced pressure, then the desired product is extracted, 3 times with 50 ml of ethyl acetate. The organic phases are combined, washed twice with 30 ml of a saturated solution of sodium chloride, dried over sodium sulphate and concentrated under reduced pressure. The 2-(2,6-difluorophenyl)-1,3-benzoxazol-4-amine is used without other purification in the following stage.
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13]([OH:20])([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=O)[N:12]=1)=[O:6])[CH:2]=[CH2:3].[BH4-].[Na+].[OH2:23].Cl>O1CCOCC1>[C:17]([O:16][CH2:14][C:13]([C:11]1[N:12]=[C:8]([NH:7][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[S:9][CH:10]=1)([OH:20])[CH3:19])(=[O:23])[CH3:18]
Reactant: O
Reactant: C=CCOC(=O)Nc1nc(C(C)(O)C(=O)OCC)cs1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C=CCOC(=O)Nc1nc(C(C)(O)COC(C)=O)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 2-(2-{[(allyloxy)carbonyl]amino}-1,3-thiazol-4-yl)-2-hydroxypropionate (2.75 g) in 1,4-dioxane (25 mL) was added sodium borohydride (0.962 g) under ice-cooling. Further, water (0.5 mL) was added thereto at room temperature, followed by stirring at room temperature for 2 hours. Concentrated hydrochloric acid (8 mL) was added thereto at an internal temperature of 20° C. or lower under ice-cooling, followed by concentration. A white solid was separated by filtration while washing the obtained residue with methanol. The obtained white solid was dissolved in pyridine (15 mL), and acetic anhydride (2.59 mL) was added thereto at room temperature, followed by stirring for 2.5 hours. To the reaction mixture was added water at room temperature, followed by extraction with ethyl acetate. The organic layer was sequentially washed with 1 M hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated brine, and then dried over anhydrous magnesium sulfate. After concentration, 2-(2-{[(allyloxy)carbonyl]amino}-1,3-thiazol-4-yl)-2-hydroxypropyl acetate (2.71 g) was obtained as a pale yellow oily substance.
Reaction SMILES: C1(C2N[C:9]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH2:24])[CH:19]=3)=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)N=2)C=CC=CC=1.N([O-])=O.[Na+].[C:29]([O-:32])(O)=[O:30].[Na+].[OH2:34]>>[O:34]=[C:10]([C:12]1[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=1)[CH2:9][C:18]1[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C:29](=[O:30])[O:32][C:12]([CH3:17])([CH3:13])[CH3:10])[CH:19]=1
Reactant: Nc1cc(-c2[nH]c(-c3ccccc3)nc2-c2ccncc2)ccn1
Reactant: O
Reactant: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)Nc1cc(CC(=O)c2ccncc2)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
The 4-[2-phenyl-4-(4-pyridinyl)-1H-imidazol-5-yl]-2-pyridinamine (86 mg, 0.27 mmol) was dissolved in 1.5 mL water containing 0.1 mL conc. Sulfuric acid and was treated with NaNO2 (24 mg, 0.38 mmol) and stirred 60 minutes. Another 7 mg NaNO2 (0.01 mmol) was added and the reaction was heated over a steam bath for 5 min. then was cooled to r.t. The reaction was basified with sat. NaHCO3 and was extracted with ethyl acetate. The combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure to give a pale yellow solid which was triturated in ether to give 27 mg (31%) of the title compound as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:12][CH2:11][CH2:10]2)=[CH:4][C:3]=1[C:13]1[CH:14]=[C:15]([CH:30]=[CH:31][N:32]=1)[C:16]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)=[O:17].[CH3:33][N:34]([CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1)[C:35]([C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=1)[C:40](O)=[O:41])=[O:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:9]1([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:40](=[O:41])[C:39]3[CH:43]=[CH:44][CH:45]=[C:37]([C:35]([N:34]([CH3:33])[CH2:46][CH2:47][N:48]4[CH2:49][CH2:50][O:51][CH2:52][CH2:53]4)=[O:36])[CH:38]=3)=[C:3]([C:13]3[CH:14]=[C:15]([C:16](=[O:17])[NH:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=4)[CH:30]=[CH:31][N:32]=3)[CH:4]=2)[CH2:10][CH2:11][CH2:12]1
Reactant: Nc1ccc(OC2CCC2)cc1-c1cc(C(=O)NCc2cccc(C(F)(F)F)c2)ccn1
Reactant: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Nc2ccc(OC3CCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 56.9 %

Procedure:
A mixture of 26 mg of 2-(2-amino-5-cyclobutoxyphenyl)-N-(3-(trifluoromethyl)benzyl)isonicotinamide, 21 mg of 3-(methyl(2-morpholinoethyl)carbamoyl)benzoic acid, 27 mg of HATU, and 63 μL of DIEA in 0.2 mL of DMF was stirred at 60° C. for 2 h. The product was isolated by reverse phase chromatography eluting with 0.05% TFA in a water/acetonitrile gradient. This procedure gave 24 mg of a yellow solid. 1H NMR (400 MHz, CD3OD, ppm): δ 9.46 (t, J=5.8 Hz, 1H), 8.85 (d, J=5.3 Hz, 1H), 8.26 (s, 1H), 8.15 (d, J=9.0 Hz, 1H), 8.05 (s, 1H), 8.01 (d, J=7.8 Hz, 1H), 7.85-7.80 (m, 1H), 7.80-7.47 (m, 6H), 7.31 (d, J=2.7 Hz, 1H), 7.00 (dd, J=8.9, 2.6 Hz, 1H), 4.83-4.71 (m, 1H), 4.67 (s, 2H), 4.09 (s, 2H), 3.96 (m, 2H), 3.77 (m, 4H), 3.52 (t, J=4.9 Hz, 2H), 3.24 (s, 2H), 3.07 (s, 3H), 2.59-2.39 (m, 2H), 2.25-2.04 (m, 2H), 1.93-1.60 (m, 2H). MS (ESI, m/z) 716.26 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.[F:16][C:17]([F:30])([F:29])[C:18]1[CH:19]=[C:20]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[NH2:21]>>[F:16][C:17]([F:29])([F:30])[C:18]1[CH:19]=[C:20]([NH:21][C:5](=[O:7])[C:4]2[CH:8]=[C:9]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:10]=[CH:11][C:3]=2[O:2][CH3:1])[CH:22]=[C:23]([C:25]([F:26])([F:28])[F:27])[CH:24]=1
Reactant: COc1ccc(S(N)(=O)=O)cc1C(=O)O
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: COc1ccc(S(N)(=O)=O)cc1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 24.2 %

Procedure:
Using 2-methoxy-5-sulfamoylbenzoic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 24 gave the title compound.
Reaction SMILES: C(C1C=CC2OC(C)(C)C=C([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:16][N+:15]=3[O-])C=2C=1)#N.ClC1C=CC(C2C=CC=CC=2)=CN=1.[IH:41]>>[I:41][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][N:15]=1
Reactant: CC1(C)C=C(c2ccc(-c3ccccc3)c[n+]2[O-])c2cc(C#N)ccc2O1
Reactant: I
Agent: Clc1ccc(-c2ccccc2)cn1
Product: Ic1ccc(-c2ccccc2)cn1

Procedure:
The 2,2-dimethyl-4(5-phenyl-2-pyridyl)-2H-1-benzopyran-6-carbonitrile used as the starting material was prepared as follows: (A) 15.98 g of 2-chloro-5-phenylpyridine were dissolved in 150 ml of 55% aqueous hydroiodic acid and the solution was heated at reflux for 2 hours. Upon cooling a solid precipitated and this was filtered off and washed with water. The solid was partitioned between diethyl ether and 2M sodium hydroxide solution, and the organic phase was dried over sodium sulphate and evaporated to give 15.87 g of 2-iodo-5-phenylpyridine which was used without further purification. (B) In an analogous manner to that described in Example 6 (A) and (B), from 2-iodo-5-phenylpyridine and 4-(1,1-dimethyl-2-propynyloxy)benzonitrile there was obtained 2,2-dimethyl-4-(5-phenyl-2-pyridyl)-2H-1-benzopyran -6-carbonitrile.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[N:11]=[C:10]([C:12]2[N:13]=[C:14]([NH:17][C:18]([NH2:20])=[S:19])[S:15][CH:16]=2)[CH:9]=[CH:8][CH:7]=1)(=[O:3])[CH3:2].[CH3:21][I:22].CO>O1CCCC1>[IH:22].[C:1]([NH:4][CH2:5][C:6]1[N:11]=[C:10]([C:12]2[N:13]=[C:14]([N:17]=[C:18]([NH2:20])[S:19][CH3:21])[S:15][CH:16]=2)[CH:9]=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCc1cccc(-c2csc(NC(N)=S)n2)n1
Reactant: CI
Solvent: C1CCOC1
Solvent: CO
Product: CSC(N)=Nc1nc(-c2cccc(CNC(C)=O)n2)cs1
Product: I

Procedure:
A mixture of 4-(6-acetylaminomethylpyridin-2-yl)-2-thioureidothiazole (5.3 g) and methyl iodide (1.2 ml) in a solution of methanol (53 ml) and tetrahydrofuran (25 ml) was heated under reflux for 4.5 hours. The solvent was removed by concentration in vacuo and resulting residue was triturated with ethyl acetate to give 4-(6-acetylaminomethylpyridin-2-yl)-2-[(amino)(methylthio)methyleneamino]thiazole hydriodide.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][NH:9][C:10](=O)OC(C)(C)C)[CH2:3][CH2:2]1.N1(CCNC(=O)OC(C)(C)C)CCNCC1.Br[C:34]1[C:43]2[C:38](=[CH:39][CH:40]=[C:41]([O:44][CH3:45])[CH:42]=2)[N:37]=[CH:36][C:35]=1[F:46].BrC1C(F)=CN=C2C=1N=C(OC)C=C2.[O:61]=[C:62]1[CH2:67][O:66][C:65]2[CH:68]=[CH:69][C:70](C=O)=[N:71][C:64]=2[NH:63]1.O=C1CSC2C=CC(C=O)=NC=2N1>>[F:46][C:35]1[CH:36]=[N:37][C:38]2[C:43]([C:34]=1[N:1]1[CH2:2][CH2:3][CH:4]([CH2:7][CH2:8][NH:9][CH2:10][C:70]3[CH:69]=[CH:68][C:65]4[O:66][CH2:67][C:62](=[O:61])[NH:63][C:64]=4[N:71]=3)[CH2:5][CH2:6]1)=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: CC(C)(C)OC(=O)NCCC1CCNCC1
Reactant: COc1ccc2ncc(F)c(Br)c2c1
Agent: CC(C)(C)OC(=O)NCCN1CCNCC1
Agent: COc1ccc2ncc(F)c(Br)c2n1
Agent: O=Cc1ccc2c(n1)NC(=O)CS2
Product: COc1ccc2ncc(F)c(N3CCC(CCNCc4ccc5c(n4)NC(=O)CO5)CC3)c2c1
Yield: 32.7 %

Procedure:
The title compound (100 mg, 33%) was prepared as a yellow solid according to Example 1, except substituting the following three reagents: 1,1-dimethylethyl [2-(4-piperidinyl)ethyl]carbamate (1 g, 4.38 mmol) [prepared according to Ambler, J.; et. al. Bioorg. Med. Chem. Lett. 1999, 9, 9, 1317.] for 1,1-dimethylethyl [2-(1-piperazinyl)ethyl]carbamate, 4-bromo-3-fluoro-6-(methyloxy)quinoline (2.25 g, 8.77 mmol) for 8-bromo-7-fluoro-2-(methyloxy)-1,5-naphthyridine and 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (117 mg, 0.657 mmol) for 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde: LCMS (ES) m/e 482 (M+H)+; 1H NMR (400 MHz, CD3OD) δ 8.47 (d, J=4.5 Hz, 1H), 7.87 (d, J=9.1 Hz, 1H), 7.40 (d, J=2.7 Hz, 1H), 7.34 (dd, J=2.7, 6.3 Hz, 1H), 7.29 (d, J=8.0 Hz, 1H), 6.99 (d, J=8.0 Hz, 1H), 4.66 (s, 2H), 3.97 (s, 3H), 3.79 (s, 2H), 3.35-3.50 (m, 2H), 3.26-3.30 (m, 2H), 2.71-2.75 (m, 2H), 1.87-1.90 (m, 2H), 1.62-1.66 (m, 3H), 1.52-1.55 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH2:28])=[N:8][CH:9]=[C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][CH:16]=[C:15]3[C:21]2[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH:26]=2)[CH:11]=1>CO.C(O)(=O)C.C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH2:28])=[N:8][CH:9]=[C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][CH:16]=[C:15]3[CH:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)[CH:11]=1
Reactant: CN1CC=C(c2c[nH]c3ccc(-c4cnc(N)c(OCc5c(Cl)cccc5Cl)c4)cc23)CC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: CN1CCC(c2c[nH]c3ccc(-c4cnc(N)c(OCc5c(Cl)cccc5Cl)c4)cc23)CC1

Procedure:
To a de-gassed solution of 3-(2,6-dichloro-benzyloxy)-5-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-5-yl]-pyridin-2-ylamine (example I-61, 130 mg, 0.27 mmol) in methanol (50 mL) and acetic acid (5 mL) was added 10% Pd/C (50 mg). The solution was degassed and charged with hydrogen for three times, and then was stirred under hydrogen balloon for over night. The mixture was filtered through a celite pad, washed with methanol, and then condensed. The residue was dissolved in ethyl acetate, washed with sat. NaHCO3 and brine, dried over Na2SO4, and condensed. The crude product was purified on a silica gel column eluting with dichloromethane-methanol-triethyl amine (95:5:0.1) to provide 3-(2,6-dichloro-benzyloxy)-5-[3-(1-methyl-piperidin-4-yl)-1H-indol-5-yl]-pyridin-2-ylamine as a white solid.
Reaction SMILES: C[O-].[Na+].[CH3:4][O:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([NH2:12])=[S:11].[C:13]([CH2:15][C:16](OCC)=[O:17])#[N:14]>C(O)C>[NH2:14][C:13]1[N:9]([CH2:8][CH2:7][CH2:6][O:5][CH3:4])[C:10](=[S:11])[NH:12][C:16](=[O:17])[CH:15]=1
Reactant: CCOC(=O)CC#N
Reactant: COCCCNC(N)=S
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: COCCCn1c(N)cc(=O)[nH]c1=S
Yield: 48.3 %

Procedure:
Sodium methoxide (0.81 g, 21.2 mmol, 1.05 eq.) was added to a solution of 3-methoxypropylthiourea (3.00 g, 20.2 mmol) in ethanol (10 mL). Ethyl cyanoacetate (2.18 mL, 20.2 mmol) in ethanol (10 mL) was added and the resulting white slurry was heated to reflux for 2.5 h. The solvent was evaporated and the remaining pale brown oil was treated with 2M acetic acid (15 mL). The white crystals were filtered off and washed with acetic acid to give the title compound (2.10 g, 48%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]2C(=O)C3=CC=CC=C3C2=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(O)C.O.NN>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCS(=O)(=O)c1ccc(Cl)cc1
Agent: NN
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: NCCCCCS(=O)(=O)c1ccc(Cl)cc1
Yield: 119.8 %

Procedure:
Then, 4.0 g (10.2 mmol) of 1-(4-chlorophenylsulfonyl)-5-phthalimidopentane was dissolved in 120 ml of dichloromethane and 20 ml of ethanol and stirred together with 6 ml of 80% hydrazine hydrate at room temperature for 36 hours. The impurities were filtered out, and the filtrate was evaporated in vacuo to give 3.2 g of the title compound.
Reaction SMILES: C([Li])CCC.CCCCCC.[CH2:12]([C@H:19]1[CH2:23][O:22][C:21](=[O:24])[NH:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:25][CH2:26][CH2:27][CH2:28][C:29](Cl)=[O:30].[Cl-].[NH4+]>O1CCCC1>[CH2:12]([C@H:19]1[CH2:23][O:22][C:21](=[O:24])[N:20]1[C:29](=[O:30])[CH2:28][CH2:27][CH2:26][CH3:25])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: CCCCC(=O)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reaction time: 0.33 h
Yield: 101.2 %

Procedure:
90 ml of a solution of n-butyllithium in n-hexane (1.60 mol/l) (144 mmol) was added to a solution of 25.0 g of (S)-4-benzyl-2-oxazolidinone (141 mmol) in tetrahydrofuran (600 ml) under a nitrogen atmosphere and at −78° C. over 10 minutes, and the mixture was stirred at the same temperature for 20 minutes. Then, 19.0 ml of n-valeryl chloride (159 mmol) was added over 10 minutes. The mixture was stirred at the same temperature for 20 minutes and then further stirred at room temperature for three hours. 90 ml of a saturated ammonium chloride aqueous solution was added to the reaction mixture, and the mixture was further stirred at room temperature for 15 minutes. The reaction mixture was concentrated under reduced pressure and diluted with 300 ml of water, followed by extraction with methylene chloride. Then, the organic layer was washed with a saturated sodium bicarbonate aqueous solution and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain 37.3 g of the crude title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]2[C:16]3[CH:15]=[C:14]([C:17]([O:19]C)=[O:18])[NH:13][C:12]=3[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[OH-].[Li+].C1COCC1>CO>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]2[C:16]3[CH:15]=[C:14]([C:17]([OH:19])=[O:18])[NH:13][C:12]=3[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)c1cc2c([nH]1)CCC2c1cccc(C#N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1cccc(C2CCc3[nH]c(C(=O)O)cc32)c1
Yield: 44 %

Procedure:
The title compound was synthesized from methyl 4-(3-cyanophenyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.021 g, 0.079 mmol) and lithium hydroxide (0.035 g, 0.83 mmol), according to General Procedure 7. A 1:1 mixture of THF and methanol (2 mL) was used. The resulting product was purified by reverse phase HPLC, eluting with a gradient of 40-80% MeOH: water (with 0.1% formic acid) to afford a light pink solid: 8.8 mg (44% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.21 (dd, J=6.35, 2.34 Hz, 1H), 2.79 (s, 2H), 2.91-3.02 (m, 1H), 4.26 (s, 1H), 6.52 (s, 1H), 7.42-7.48 (m, 1H), 7.49-7.56 (m, 3H); LCMS (ESI−) 251.2 (M−H); HPLC (UV=100%), (ELSD=100%).
Reaction SMILES: I[CH3:2].[CH2:3]([N:10]1[CH:16]2[CH2:17][CH2:18][CH:11]1[CH2:12][NH:13][CH2:14][CH2:15]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C1COCC1.CCOCC>[CH2:3]([N:10]1[CH:16]2[CH2:17][CH2:18][CH:11]1[CH2:12][N:13]([CH3:2])[CH2:14][CH2:15]2)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CI
Reactant: c1ccc(CN2C3CCNCC2CC3)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN1CCC2CCC(C1)N2Cc1ccccc1

Procedure:
Neat Iodomethane (0.173 ml, 2.77 mmol) was added dropwise to a stirred solution of 9-benzyl-3,9-diazabicyclo[4.2.1]nonane (0.4 g, 1.849 mmol) and TEA (2.58 ml, 18.49 mmol) in THF (5 ml). The resultant suspension was stirred at rt for 3 hrs and diluted with ether and then filtered. The filtrate was evaporated to dryness to afford 9-benzyl-3-methyl-3,9-diazabicyclo[4.2.1]nonane as a light yellow oil. LC/MS: m/e 231 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2([C:23]3[CH:28]=[CH:27][C:26](SC)=[CH:25][CH:24]=3)[O:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[O:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[O:32][S:33]([O-:35])=O.[K+].[CH3:37]O>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2([C:23]3[CH:28]=[CH:27][C:26]([S:33]([CH3:37])(=[O:35])=[O:32])=[CH:25][CH:24]=3)[O:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[O:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CSc1ccc(C2(C3CCN(C(=O)OC(C)(C)C)CC3)Oc3ccccc3O2)cc1
Reactant: O=S([O-])OO
Reactant: CO
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CCC(C2(c3ccc(S(C)(=O)=O)cc3)Oc3ccccc3O2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To 4-[2-(4-methylsulfanyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 272) (166 mg, 0.375 mmol) in MeOH (5 mL) cooled to 0° C. was added OXONE® (461 mg, 0.75 mmol) and the mixture was stirred at room temperature for 2 hours. A second aliquot of OXONE® (461 mg, 0.75 mmol) was added and the mixture stirred at room temperature for 24 hours. Standard work-up gave 4-[2-(4-methanesulfonyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester as a white solid (172 mg, 100%).
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)([O-:3])=[O:2].I[CH:10]([CH3:12])[CH3:11].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH:10]([N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[CH:6]1)([CH3:12])[CH3:11]
Reactant: O=[N+]([O-])c1c[nH]cn1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)n1cnc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.2 %

Procedure:
4-nitroimidazole (0.500 g, 4.42 mmol), 2-iodopropane (0.553 ml, 5.53 mmol) and powdered K2CO3 (0.917 g, 6.63 mmol) were combined and stirred in DMF (25 ml) at 50° C. After 5 h, the reaction was cooled to RT. The reaction was diluted with EtOAc and filtered to remove inorganic salts, rinsing forward with EtOAc. The filtrate was evaporated to near dryness. The residue was diluted in EtOAc, washed with H2O (2×) and brine (1×), dried (MgSO4) and evaporated to afford 1-isopropyl-4-nitro-1H-imidazole (0.66 g, 96% yield) as a pale yellow oil. 1H NMR (400 MHz, DMSO-d6): δ 8.51 (s, 1H) 7.98 (s, 1H), 4.52-4.49 (m, 1H), 1.44 (d, 6H); MS (ESI) m/z: 156.0 (M+H+), 178.0 (M+Na+).