Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7](/[CH:8]=[C:9](\[CH2:15][CH2:16][CH2:17][CH3:18])/[C:10]([O:12]CC)=[O:11])=[C:6]([O:19][CH3:20])[C:5]([O:21][CH3:22])=[C:4]([O:23][CH3:24])[C:3]=1[O:25][CH3:26]>CCOCC>[CH3:1][C:2]1[C:7](/[CH:8]=[C:9](\[CH2:15][CH2:16][CH2:17][CH3:18])/[C:10]([OH:12])=[O:11])=[C:6]([O:19][CH3:20])[C:5]([O:21][CH3:22])=[C:4]([O:23][CH3:24])[C:3]=1[O:25][CH3:26]
Reactant: CCCC/C(=C\c1c(C)c(OC)c(OC)c(OC)c1OC)C(=O)OCC
Solvent: CCOCC
Product: CCCC/C(=C\c1c(C)c(OC)c(OC)c(OC)c1OC)C(=O)O

Procedure:
Compound 9e was prepared from 8e (0.166 g, 0.453 mmol) as described above for 9a using Method B to give 0.144 g (0.426 mmol, 94%) of the product as a yellow amorphous solid following flash chromatography (2:3 Et2O:hexanes 0.5% AcOH) and recrystallization from Et2O/hexanes.
Reaction SMILES: [OH-].[CH2:2]([N+:18]([CH3:21])([CH3:20])[CH3:19])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[CH2:22]([O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[C:27]([OH:34])[CH:26]=1)[CH3:23].[OH-].[Na+]>>[CH2:22]([O:24][C:25]1[CH:26]=[C:27]([OH:34])[C:28](=[CH:32][CH:33]=1)[C:29]([O-:31])=[O:30])[CH3:23].[CH2:2]([N+:18]([CH3:21])([CH3:19])[CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCOc1ccc(C(=O)O)c(O)c1
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Na+]
Agent: [OH-]
Product: CCOc1ccc(C(=O)[O-])c(O)c1

Procedure:
The last third of the cetyl-trimethylammonium hydroxide solution is neutralized with 12.39 g of 4-ethoxy-2-hydroxy-benzoic acid (the equivalent weight of which has been determined as 185.8 by titration with 0.1N sodium hydroxide solution) by scattering in as a powder. The resulting yellow solution in methanol is concentrated to dryness. 31.1 g of a slightly brownish residue are obtained, which can be purified by recrystallization from 300 ml of ethyl acetate several times. Cetyl-trimethylammonium 4-ethoxysalicylate is obtained in (slightly reddish) crystals (titration with perchloric acid in glacial acetic acid gives the expected equivalent weight).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]=[C:19]3[S:23][C:22](=[O:24])[NH:21][C:20]3=[O:25])=[CH:14][CH:13]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[C:1]1([CH2:7][CH2:8][CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15]([CH2:18][CH:19]3[S:23][C:22](=[O:24])[NH:21][C:20]3=[O:25])=[CH:16][CH:17]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1NC(=O)C(=Cc2ccc(C(=O)CCCc3ccccc3)cc2)S1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: O=C1NC(=O)C(Cc2ccc(C(=O)CCCc3ccccc3)cc2)S1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.5 %

Procedure:
To a solution of the title product of Example 66 (145 mg, 0.408 mmol) in acetone (10 ml) at 0° C. was added in a dropwise fashion Jones' Reagent (2.67M, 0.39 ml, 1.0 mmol). After stirring for 2 hours at room temperature, the reaction was quenched by the addition of isopropanol (1 ml) followed by water (20 ml), and stirred 10 minutes. The blue solution was decanted and extracted with EtOAc (2×20 ml). The combined organic layers were washed with water (20 ml), brine (20 ml), dried (MgSO4), filtered and concentrated to afford the present title product (129 mg, 90%); m.p. 120°-122° C.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][C:7]2[C:16]([OH:17])=[C:15]([C:18]([OH:20])=[O:19])[C:14]3[C:9](=[C:10]([C:21]4[CH:26]=CC=[CH:23][CH:22]=4)[CH:11]=[CH:12][CH:13]=3)[N:8]=2)=[CH:4][CH:3]=1.[O:29]1C=CC(C2C=CC=C3C=2NC(=O)C3=O)=C1.C(OCC(=O)CC1C=CC(Cl)=CC=1)(=O)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:16]([OH:17])=[C:15]([C:18]([OH:20])=[O:19])[C:14]3[C:9](=[C:10]([C:21]4[CH:22]=[CH:23][O:29][CH:26]=4)[CH:11]=[CH:12][CH:13]=3)[N:8]=2)=[CH:27][CH:28]=1
Reactant: O=C1Nc2c(cccc2-c2ccoc2)C1=O
Reactant: O=C(O)c1c(O)c(Cc2ccc(Cl)cc2)nc2c(-c3ccccc3)cccc12
Agent: CC(=O)OCC(=O)Cc1ccc(Cl)cc1
Product: O=C(O)c1c(O)c(Cc2ccc(Cl)cc2)nc2c(-c3ccoc3)cccc12
Yield: 15 %

Procedure:
This compound was synthesized according to the procedure described above for Compound 2, reacting 7-(fur-3-yl)isatin, Intermediate 10 (0.84 g, 3.9 mmol) with 3-(4-chlorophenyl)-2-oxopropyl acetate, Intermediate 2 (1.11 g, 4.91 mmol). The crude acid was purified as described above for Compound 3 to give pure product, a mustard-yellow powder Compound 12 (0.217 g, 15% yield): 1H NMR (400 MHz, DMSO-D6) δ 4.40 (s, 2H) 7.09 (d, J=1.8Hz, 1H) 7.39 (q, J=8.6 Hz, 4H) 7.56 (dd, J=8.46, 7.5 Hz, 1H) 7.67 (t, J=1.8 Hz, 1H) 7.84 (dd, J=7.3, 1.3 Hz, 1H) 8.07 (s, 1H) 8.30 (dd, J=8.6, 1.0 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24](=[O:39])[NH:25][CH:26]([C:32]3[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=3)[CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:47][CH2:48][F:49]>O1CCCC1>[F:49][CH2:48][CH2:47][O:38][C:35]1[CH:36]=[CH:37][C:32]([CH:26]([NH:25][C:24]([C@@H:20]2[CH2:21][CH2:22][CH2:23][N:18]([C:16](=[O:17])[CH2:15][CH2:14][CH:11]3[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]3)[CH2:19]2)=[O:39])[CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:33][CH:34]=1
Reactant: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1ccc(O)cc1
Reactant: FCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1ccc(OCCF)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 54.3 %

Procedure:
150 mg (0.28 mmol) 4-(3-{(R)-3-[1-(4-hydroxy-phenyl)-2-methoxycarbonyl-ethylcarbamoyl]-piperidin-1-yl}-3-oxo-propyl)-piperidine-1-carboxylic acid tert-butyl ester were dissolved in 3 ml tetrahydrofurane. 179 mg (0.55 mmol) cesium carbonate and 91 mg (0.52 mmol) 1-iodo-2-fluoroethane were added. The mixture was stirred at room temperature for 60 hours and filtrated. The filtrate was concentrated. Chromatography over 10 g silica gel (dichloromethane ethanol 100/0-90/10) gave 90 mg (50%) tert-butyl 4-{3-[(3R)-3-({1-[4-(2-fluoroethoxy)phenyl]-3-methoxy-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate and 40 mg starting material.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][C:14](I)=[CH:13][CH:12]=3)=[O:5])[CH3:2].[CH2:20]([O:22][P:23]([O-:27])[O:24][CH2:25][CH3:26])[CH3:21].C(N(CC)CC)C>[Pd].CN1CCCC1=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][C:14]([P:23]([O:24][CH2:25][CH3:26])([O:22][CH2:20][CH3:21])=[O:27])=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccc(I)cc12
Reactant: CCOP([O-])OCC
Agent: [Pd]
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc2c(cn1)[nH]c1ccc(P(=O)(OCC)OCC)cc12
Temperature: 90 °C
Reaction time: 12 h
Yield: 28.1 %

Procedure:
1.46 g of 6-iodo-beta-carboline-3-carboxylic-acid-ethylester is added anhydrously to a mixture of 608 g of diethylphosphite, 448 g of triethylamine, 240 mg of palladium tetrakristriphenylphosphine and 60 ml of N-methyl-2-pyrrolidone and is stirred for 12 h at 90° C. After concentration is an oil pump vacuum, the residue is chromatographed on 75 g of silica gel with methylene-chloride/acetone in the ratio of 1/1 as the eluant. The corresponding consolidated fractions are chromatographed on 25 g of silica gel with methylene-chloride/ethanol=10/2 as the eluant. 421 mg of 6-diethoxyphosphoryl-beta-carboline-3-carboxylic-acid-ethylester in the form of an oil is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][C@@H:15]3[C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][N:29]5[CH2:33][CH2:32][CH2:31][CH2:30]5)=[CH:22][CH:21]=3)([CH3:13])[C:11](=[O:34])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1.[Na].O>CO>[N:29]1([CH2:28][CH2:27][CH2:26][C:23]2[CH:24]=[CH:25][C:20]([C@H:15]3[CH2:14][C@@:12]4([CH3:13])[C@@H:8]([CH2:9][CH2:10][C@@H:11]4[OH:34])[C@H:7]4[C@H:16]3[C:17]3[CH:18]=[CH:19][C:2]([OH:1])=[CH:3][C:4]=3[CH2:5][CH2:6]4)=[CH:21][CH:22]=2)[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: C[C@]12C[C@H](c3ccc(CCCN4CCCC4)cc3)[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: [Na]
Solvent: CO
Solvent: O
Product: C[C@]12C[C@H](c3ccc(CCCN4CCCC4)cc3)[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Yield: 69.7 %

Procedure:
To a solution of 310 mg of the product obtained in example 2 in 3 ml of methanol, 54 mg of sodium borohydrure at 97% is added at 0-5° C., stirred for 1 hour at this temperature, salt water is added, it is drawn off, washed, dried and evaporated under reduced pressure until 320 mg of raw product is obtained that is purified by chromatography by eluting with the compound CH2Cl2/MeOH/NH4OH 90/10/1. 217 mg of pure expected product is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:28][C:29]1[S:30][C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:40]([F:43])([F:42])[F:41])=[CH:32][N:33]=1>C(#N)C.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:10](=[O:13])[N:11]([CH2:28][C:29]3[S:30][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[C:40]([F:43])([F:41])[F:42])=[CH:32][N:33]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Reactant: FC(F)(F)c1ccccc1-c1cnc(CBr)s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CO
Product: O=c1n(Cc2ncc(-c3ccccc3C(F)(F)F)s2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Temperature: 80 °C
Reaction time: 1 h

Procedure:
40 mg (0.13 mmol) of the compound from Example 5A were dissolved in 7 ml of acetonitrile, and 66 mg (0.20 mmol) of cesium carbonate and 42 mg (0.13 mmol) of the compound from Example 89A were added. The mixture was stirred at 80° C. for 1 h. For work-up, the mixture was cooled to RT, diluted with 5 ml of methanol and filtered. The filtrate was concentrated under reduced pressure and the crude product was then purified chromatographically [Method 19]. This gave 47 mg (66% of theory) of the target compound.
Reaction SMILES: [N:1]1[C:2]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[I:15]N1C(=O)CCC1=O>C(#N)C>[I:15][C:3]1[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[N:1][C:2]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1cn2ccccc2n1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: CCOC(=O)c1nc2ccccn2c1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.4 %

Procedure:
2.405 g (12.16 mmol) of ethyl imidazo[1,2-a]pyridine-2-carboxylate were dissolved in 60 ml of acetonitrile with magnetic stirring, to this solution were added 3.01 g (13.38 mmol) of N-iodosuccinimide. The mixture was stirred at r.t. for 1 h. The reaction mixture was treated with 50 ml of 100 mg/ml Na2S2O5 aqueous solution. The aqueous phase was extracted with 2×100 ml of ethyl acetate. The aqueous phase was neutralized by adding NaHCO3 portionwise and then extracted with 3×100 ml of ethyl acetate. The whole of the organic phases was combined and then washed with 200 ml of a saturated NaCl aqueous solution, and then dried on Na2SO4 which was then removed by filtration. The obtained filtrate was concentrated in vacuo in order to obtain 1.59 g (yield=41%) of ethyl 3-iodoimidazo[1,2-a]pyridine-2-carboxylate as a pale yellow solid. LC-MS: m/z=317 (MH+); UV purity at 254 nm=99%. 1H NMR (300 MHz, DMSO) δ 8.45 (d, J=6.9 Hz, 1H), 7.66 (d, J=9.1 Hz, 1H), 7.46 (d, J=7.0 Hz, 1H), 7.15 (d, J=6.6 Hz, 1H), 4.30 (d, J=7.1 Hz, 2H), 1.36 (d, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[CH:27][N:26]=[CH:25]3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([S:37](Cl)(=[O:39])=[O:38])[CH:32]=1>>[C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH:28]=[CH:27][N:26]=[CH:25]3)=[CH:22][CH:23]=2)[S:37]([C:33]2[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=2)(=[O:39])=[O:38])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-n3ccnc3)cc2)c1
Agent: Cl
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-n3ccnc3)cc2)S(=O)(=O)c2cccnc2)c1

Procedure:
The title compound of Step A was prepared from {3-[(4-imidazol-1-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester, prepared in Step A of Example 13l, and pyridine-3-sulfonyl chloride hydrochloride, of Preparation 2, following the method described in Example 3, Step B. 1H NMR (400 MHz, CDCl3)δ 9.04 (d, 1H), 8.80 (dd, 1H), 8.06 (d, 1H), 7.83 (s, 1H), 7.44 (dd, 1H), 7.22 (m, 6H), 7.11 (t, 1H), 6.73 (dd, 1H), 6.64 (m, 2H), 4.39 (s, 2H), 4.38 (s, 2H), 4.32 (s, 2H), 1.47 (s, 9H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH:21]1[CH2:25][NH:24][C:23](=[O:26])[CH2:22]1.N(C(OCC)=O)=NC(OCC)=O.[C:39]([OH:42])(=[S:41])[CH3:40]>O1CCCC1>[C:39]([S:41][CH:21]1[CH2:25][NH:24][C:23](=[O:26])[CH2:22]1)(=[O:42])[CH3:40]
Reactant: O=C1CC(O)CN1
Reactant: CC(O)=S
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)SC1CNC(=O)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
20-(1) 15.6 g of triphenylphosphine were added to a suspension of 3 g of 4-hydroxy-2-pyrrolidinone in 200 ml of tetrahydrofuran, and then the mixture was stirred at room temperature for 5 minutes, after which it was cooled to -20° C. A solution of 9.3 ml of diethyl azodicarboxylate in 9 ml of tetrahydrofuran was added dropwise, whilst cooling at -12° C. to -20° C., to the previous solution. The mixture was then stirred at 0°-5° C. for 5 minutes, after which it was again cooled to -20° C. 4.2 ml of thioacetic acid were then added dropwise to the mixture, whilst cooling at -18° C. to -20° C. The mixture was then warmed to 0°-5° C. and stirred at that temperature for 2 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure. The residue was purified first by column chromatography through silica gel, eluted with a 10:1 by volume mixture of ethyl acetate and methanol, and then by column chromatography through silica gel, eluted with a 2:1 by volume mixture of acetonitrile and benzene, to give 2.45 g of 4-acetylthio-2-pyrrolidinone as colorless crystals.
Reaction SMILES: [CH:1]([C:4]1[N:5]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=[C:7]([C:9]([OH:11])=O)[N:8]=1)([CH3:3])[CH3:2].[NH2:20][C@@H:21]([CH3:37])[CH2:22][N:23]1[CH:27]=[CH:26][C:25]([C:28]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[C:30]([Cl:36])[CH:29]=2)=[N:24]1>>[Cl:36][C:30]1[CH:29]=[C:28]([C:25]2[CH:26]=[CH:27][N:23]([CH2:22][C@@H:21]([NH:20][C:9]([C:7]3[N:8]=[C:4]([CH:1]([CH3:2])[CH3:3])[N:5]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=3)=[O:11])[CH3:37])[N:24]=2)[CH:35]=[CH:34][C:31]=1[C:32]#[N:33]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: CC(C)c1nc(C(=O)O)cn1COCC[Si](C)(C)C
Product: CC(C)c1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cn1COCC[Si](C)(C)C

Procedure:
The title compound was prepared using the procedure described in Example 32(e) starting from 2-isopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylic acid (0.430 g, 1.5 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.395 g, 1.5 mmol). Yield 360 mg. 1H-NMR (400 MHz; DMSO-d6): δ 0.06 (s, 9H), 0.80-0.85 (m, 2H), 1.10 (d, 3H), 1.21-1.24 (m, 6H), 3.08-3.15 (m, 1H), 3.43-3.47 (m, 2H), 4.30-4.44 (m, 3H), 5.32 (s, 2H), 6.96 (d, 1H), 7.63 (s, 1H), 7.85-7.87 (m, 2H), 7.93-7.95 (m, 2H), 8.09 (s, 1H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Br-:12].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl.CO>[Br:12][C:6]1[C:7]([NH2:11])=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][CH:2]=[N:1]2
Reactant: Nc1ccc2ncccc2c1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Nc1ccc2ncccc2c1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 31.6 %

Procedure:
To a solution of quinolin-6-ylamine (503 mg, 3.49 mmol) in dichloromethane (17 mL) and methanol (8.6 mL) was added tetra-n-butylammonium tribromide (1.68 g, 3.49 mmol). The mixture was stirred at 25° C. for 90 minutes, and then 10 5 mL of aqueous sodium thiosulfate was added. The mixture was extracted with dichloromethane, and the combined extracts were washed with water, dried (Na2SO4), filtered and concentrated to dryness under reduced pressure. Purification by flash column (hexanes/ethylacetate gradient) gave 5-bromo-quinolin-6-ylamine (246 mg, 32%).
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[NH:19][CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].Br[CH2:30][CH:31]([CH3:33])[CH3:32]>>[C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[N:19]([CH2:30][CH:31]([CH3:33])[CH3:32])[CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(Cl)cc2)c2cc[nH]c2c(=O)n1C
Reactant: CC(C)CBr
Product: CC(C)Cn1ccc2c(-c3ccc(Cl)cc3)c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c21

Procedure:
The title compound was prepared in a manner similar to that described in Example 2 from methyl 2-(tert-butoxy)-2-(4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate and 1-bromo-2-methylpropane. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.59-7.67 (m, 1H) 7.45-7.51 (m, 2H) 7.39-7.45 (m, 1H) 6.97-7.04 (m, 1H) 5.91-5.98 (m, 1H) 5.30-5.39 (m, 1H) 4.23-4.44 (m, 2H) 3.67 (s, 3H) 2.16-2.31 (m, 1H) 1.01 (s, 9H) 0.88-0.98 (m, 6H); LCMS (m/z) ES+=445 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:14]3[CH:34]=[CH:33][C:17]([O:18][C:19]4[CH:20]=[C:21]([C@@:25]5([CH3:32])[O:29][C:28](=[O:30])[NH:27][C:26]5=[O:31])[CH:22]=[CH:23][CH:24]=4)=[C:16]([CH2:35]CC)[CH:15]=3)=[CH:8][C:9](=[O:13])[O:10]2)=[CH:5][CH:4]=1.C([O-])([O-])=[O:39].[Cs+].[Cs+].O>CN(C=O)C>[CH:35]([C:16]1[CH:15]=[C:14]([C:7]2[C:6]3[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[O:10][C:9](=[O:13])[CH:8]=2)[CH:34]=[CH:33][C:17]=1[O:18][C:19]1[CH:20]=[C:21]([C@@:25]2([CH3:32])[O:29][C:28](=[O:30])[NH:27][C:26]2=[O:31])[CH:22]=[CH:23][CH:24]=1)=[O:39]
Reactant: O=C([O-])[O-]
Reactant: CCCc1cc(-c2cc(=O)oc3cc(OC)ccc23)ccc1Oc1cccc([C@@]2(C)OC(=O)NC2=O)c1
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(-c3ccc(Oc4cccc([C@@]5(C)OC(=O)NC5=O)c4)c(C=O)c3)cc(=O)oc2c1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of the product from step 1 (0.30, 1.0 mmol) and intermediate 13 (0.20, 1.0 mmol) and Cs2CO3 (0.65 g, 2.0 mmol) in DMF (5.0 mL) was stirred at 80° C. for 4 h. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with water, dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel to to give the title compound as a solid.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([Cl:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1.[NH:14]1[C:22]2[C:17](=[CH:18][C:19]([CH:23]=[O:24])=[CH:20][CH:21]=2)[CH:16]=[N:15]1>>[Cl:9][C:8]1[C:3]([CH2:2][N:14]2[C:22]3[C:17](=[CH:18][C:19]([CH:23]=[O:24])=[CH:20][CH:21]=3)[CH:16]=[N:15]2)=[N:4][CH:5]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:7]=1
Reactant: FC(F)(F)c1cnc(CBr)c(Cl)c1
Reactant: O=Cc1ccc2[nH]ncc2c1
Product: O=Cc1ccc2c(cnn2Cc2ncc(C(F)(F)F)cc2Cl)c1

Procedure:
1-(3-Chloro-5-trifluoromethyl-pyridin-2-ylmethyl)-1H-indazole-5-carbaldehyde was prepared from 2-Bromomethyl-3-chloro-5-trifluoromethyl-pyridine and 1H-indazole-5-carbaldehyde following General Procedure A.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[C:11](OCC)=O)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:43]1(=[O:53])[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:45](=[O:52])[NH:44]1.C(OC(N=NC(OC(C)C)=O)=O)(C)C.C1(C)C=CC=CC=1>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:10][C@H:9]2[CH2:11][N:44]2[C:45](=[O:52])[C:46]3[C:51](=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:43]2=[O:53])=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1ccc(F)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1C[C@@H]1C[C@H]1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
trans-Ethyl 2-(4-Fluorophenyl)cyclopropane-1-carboxylate (793 mg, 4.57 mmol) in tetrahydrofuran (7 mL) was stirred with lithium aluminium hydride (173 mg, 4.57 mmol) under cooling with ice for 10 minutes. After addition of 1 M aqueous sodium hydroxide, the reaction mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (10 mL), mixed with triphenylphosphine (999 mg, 3.81 mmol), isoindoline-1,3-dione (560 mg, 3.81 mmol) and azodicarboxylic acid diisopropyl ester-toluene solution (1.9 M, 2.00 mL, 3.81 mmol) under cooling with ice, and the reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1 (v/v)) to give the title compound as a colorless solid (975 mg, yield 87% (2 steps)).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:13][C:14]1[S:15][CH:16]=[C:17]([C:19](O)=[O:20])[N:18]=1.C(N(CC)CC)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:19]([C:17]3[N:18]=[C:14]([CH3:13])[S:15][CH:16]=3)=[O:20])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: Cc1nc(C(=O)O)cs1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)cs1
Yield: 68 %

Procedure:
A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869 mmol, Example 1, Step H), 2-methylthiazole-4-carboxylic acid (311 mg, 2.17 mmol), and triethylamine (606 μL, 4.35 mmol) in CH2Cl2 (10 mL) at room temperature was treated with BOP—Cl (203 mg, 2.17 mmol). After 1 hour the solid formed was filtered and washed with CH2Cl2 (3×4 mL) to provide N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylthiazole-4-carboxamide (210 mg, 68% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 12.14 (s, 1H), 9.83 (s, 1H), 8.38 (d, 1H), 8.26 (s, 1H), 7.74 (d, 1H), 2.77 (s, 3H); LCMS (APCI+) m/z 354.9, 356.9 (M+H)+, Retention time=3.39 minutes (Method 2).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][N:8]=2)=[CH:4][CH:3]=1>O=[Pt]=O.CO>[Br:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[N:8]=[CH:9][C:10]([NH2:13])=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(Br)cc2)nc1
Agent: O=[Pt]=O
Solvent: CO
Product: Nc1ccc(Oc2ccc(Br)cc2)nc1
Temperature: 23 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
A mixture of 2-(4-bromo-phenoxy)-5-nitro-pyridine (6.0 g, 22.7 mmol), 200 mL of methanol and 50 mg of PtO2 was shaken under 50 psi of H2 for 1 hour at 23° C. The mixture was filtered through a pad of celite® and the filtrate was concentrated in vacuo, affording 6 g of 6-(4-bromo-phenoxy)-pyridin-3-ylamine. 1H NMR (CD3OD, 500 MHz): 7.65 (d, 1H, J=3.5 Hz), 7.48 (d, 2H, J=8.5 Hz), 7.25 (dd, 1H, J=3.5, 9.0 Hz), 6.91 (d, 2H, J=9.0 Hz), 6.80 (d, 1H, J=9.0 Hz) ppm. MS (APCl, m/z): 265 [M+H]+.