Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([C:14](=[O:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:11]=[CH:10][C:3]=1[C:4]([O:6]C(C)C)=[O:5].O1CCCC1.O.[OH-].[Li+].Cl>C(O)(C)C.O>[Cl:1][C:2]1[CH:13]=[C:12]([C:14](=[O:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:11]=[CH:10][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCCCCCCCCCCCCCCCCC(=O)c1ccc(C(=O)OC(C)C)c(Cl)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCC(=O)c1ccc(C(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The product from Example 10 (270 mg) was suspended in 10 ml of isopropyl alcohol and warmed. 20 ml of tetrahydrofuran was added. 200 mg of lithium hydroxide monohydrate in 3 ml of water was added followed by an additional 5 ml of water. The reaction mixture was stirred at room temperature for about 20 hours and 20 ml of 10% hydrochloric acid was added. The organic solvents were removed using a rotary evaporator and the residue was extracted with two 50 ml portions of ethyl ether. The ether extracts were combined, dried over sodium sulfate, filtered and the solvent removed under a nitrogen gas stream. The product is a white solid identical with the product disclosed in Example 15 in U.S. Pat. No. 4,469,885.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.Br[CH2:16][CH2:17][O:18][CH3:19]>CN(C)C=O.O>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:16][CH2:17][O:18][CH3:19])=[CH:10][CH:9]=1
Reactant: Oc1ccc(Br)cc1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1ccc(Br)cc1
Temperature: 60 °C
Reaction time: 17 h
Yield: 97.3 %

Procedure:
Potassium carbonate (2.4 g, 17.3 mmol) was suspended in N,N-dimethyl formamide (15 mL). 4-bromophenol (1.00 g, 5.78 mmol) and 1-bromo-2-methoxyethane (0.964 g, 6.94 mmol) were added into the reaction sequentially and the resulting mixture was stirred at 60° C. for 17 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (50 mL) dried over sodium sulfate and evaporated to give the title compound (1.3 g, 99%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[C:16](Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]>O1CCCC1>[CH3:18][C:17]([CH3:20])([CH3:19])[C:16]([NH:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1)=[O:21]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1cccnc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cccnc1NC(=O)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 76.8 %

Procedure:
2-Amino-3-methylpyridine (108 g) and triethylamine (180 ml) were dissolved in tetrahydrofuran (500 ml) and the solution cooled to 0° C. in an acetone/ice bath. A solution of pivaloyl chloride (135.4 ml) in tetrahydrofuran (250 ml) was added over 70 minutes at such a rate that the temperature remained between 0° C. and 5° C. The mixture was aged at 0° C. for 15 minutes, allowed to warm to room temperature and aged for 3 hours. The reaction mixture was quenched into water (1 liter), the phases separated and the aqueous phase extracted with ethyl acetate (2×200 ml). The organic phases were combined, washed with saturated sodium bicarbonate solution (2×200 ml), brine (200 ml) and dried (sodium sulphate). The solvent was removed under reduced pressure and the solid residue flushed with hexane (100 ml). The solid was dissolved in hot hexane, filtered and allowed to crystallise. The title compound was collected by filtration, washed with hexane (200 ml) and dried (147.4 g, 76.8% yield; mp 90°-92° C.).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].I[CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:24][CH:23]=2)=[CH:18][C:17]=1[C:33]1[CH:42]=[CH:41][C:40]2[C:39]([CH3:44])([CH3:43])[CH2:38][CH2:37][C:36]([CH3:46])([CH3:45])[C:35]=2[CH:34]=1.O>C(#N)C>[CH:1]([NH:4][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:27]=2)=[CH:18][C:17]=1[C:33]1[CH:42]=[CH:41][C:40]2[C:39]([CH3:44])([CH3:43])[CH2:38][CH2:37][C:36]([CH3:46])([CH3:45])[C:35]=2[CH:34]=1)([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCI)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1ccc(-c2ccc(OCCCNC(C)C)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Yield: 30.3 %

Procedure:
430 μl (5 mmol) of isopropylamine and 420 mg (3 mmol) of potassium carbonate are added to a solution of 600 mg (1 mmol) of ethyl 4′-(3-iodopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate in 50 ml of acetonitrile. The reaction mixture is stirred at reflux overnight. The reaction is stopped by adding water and is then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then purified by chromatography on silica gel (50/50 heptane/ethyl acetate). 160 mg of ethyl 4′-(3-isopropylaminopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate are obtained in the form of a yellowish solid (m.p.=171° C., yield=30%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[N:8]([C:9]=1[S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:6][S:5]2.[OH-].[NH4+:15]>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]2[N:8]([C:9]=1[S:10]([NH2:15])(=[O:12])=[O:11])[CH:7]=[CH:6][S:5]2
Reactant: O=S(=O)(Cl)c1c(Cl)nc2sccn12
Reactant: [NH4+]
Agent: [OH-]
Solvent: CC#N
Product: NS(=O)(=O)c1c(Cl)nc2sccn12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 0.7 %

Procedure:
2 g (1 mol equiv.) 6-Chloro-imidazo[2,1-b]thiazole-5-sulfonyl chloride was dissolved in 20 mL acetonitrile and cooled to 0° C. Dropwise, 3.7 mL (3 mol equiv.) ammoniumhydroxide was added and the reaction mixture was stirred at room temperature for 10 min, during which a white precipitate was formed. Volatiles were removed under reduced pressure, and the solid residue was washed with water and dried in vacuo affording 1.62 g (88%) 6-chloro-imidazo[2,1-b]thiazole-5-sulfonic acid amide. 1H NMR (400 MHz, DMSO-d6) δ 7.62 (d, J=4.6 1H), 7.98 (d, J=4.6 Hz, 1H), 8.00 (br.s., 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[CH3:9][O:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:9][O:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=2)[CH:13]=1
Reactant: Brc1cccc(Br)n1
Reactant: COC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Oc2cccc(Br)n2)c1
Temperature: 120 °C
Reaction time: 3 h
Yield: 96.8 %

Procedure:
A solution of 2.37 g of 2,6-dibromopyridine and 1.52 g of 3-hydroxybenzoic acid methyl ester in 10 ml of dimethylformamide is mixed with 6.6 g of cesium carbonate and heated to 120° C. with stirring for 3 hours. The reaction mixture is filtered on diatomaceous earth, rewashed with dichloromethane and the filtrate is concentrated by evaporation in a vacuum. The residue is distilled on a bulb tube at 140°-150° C. and 0.04 mbar. 2.98 g of 3-(6-bromo-2-pyridyloxy)-benzoic acid methyl ester of melting point 68°-69° C. is obtained.
Reaction SMILES: [CH:1]1([C:10]([OH:12])=[O:11])[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([OH:9])=O)[CH2:2]1>C(OC(=O)C)(=O)C>[CH:1]12[CH2:2][CH:3]([CH2:4][CH2:5][CH2:6]1)[C:7](=[O:9])[O:12][C:10]2=[O:11]
Reactant: O=C(O)C1CCCC(C(=O)O)C1
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)C2CCCC1C2
Temperature: 25 °C
Yield: 65.8 %

Procedure:
10 g (58.2 mmol) 1,3-cyclohexane dicarboxylic acid were suspended in acetic anhydride (40 ml) and refluxed during 5 h. The solution was then cooled to room temperature and the solvents were removed in vacuo. The residue was then dissolved in a mixture of heptane (20 ml) and toluene (20 ml) and the solution was cooled to 4° C. The precipitated solid was then collected by filtration and washed with pentane to give 5.9 g of the titled compound as white needles.
Reaction SMILES: [F:1][CH:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:5])=O.Br.[NH:15]1[CH2:19][CH2:18][C@H:17]([S:20][C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)[CH2:16]1>>[F:1][CH:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([N:15]1[CH2:19][CH2:18][C@H:17]([S:20][C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)[CH2:16]1)=[O:5]
Reactant: Oc1ccc(S[C@H]2CCNC2)cc1
Reactant: O=C(O)C(F)CCc1ccccc1
Agent: Br
Product: O=C(C(F)CCc1ccccc1)N1CC[C@H](Sc2ccc(O)cc2)C1

Procedure:
The title compound, MS: m/e=360.2 (M+H+) was prepared from (RS)-2-fluoro-4-phenyl-butyric acid and (3S)-4-(pyrrolidin-3-yl-sulfanyl)-phenol hydrobromide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]#[N:28])[CH:22]=3)=[O:19])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(C1C=C(NC(=O)N)C=CC=1)#N.[NH:41]1[CH2:46][CH2:45][CH:44]([OH:47])[CH2:43][CH2:42]1>Cl.O1CCOCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([N:41]4[CH2:46][CH2:45][CH:44]([OH:47])[CH2:43][CH2:42]4)=[NH:28])[CH:22]=3)=[O:19])=[CH:15][CH:16]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: OC1CCNCC1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)c3ccc(Br)cc3)cc2)c1
Agent: Cl
Agent: N#Cc1cccc(NC(N)=O)c1
Solvent: C1COCCO1
Solvent: CO
Product: N=C(c1cccc(NC(=O)Nc2ccc(S(=O)(=O)c3ccc(Br)cc3)cc2)c1)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under argon atmosphere, 1 equivalent of 1-(4-(4-bromophenylsulfonyl)phenyl)-3-(3-cyanophenyl)urea (VIII) [or a correspondent 14444-substituted-phenylsulfonyl)phenyl)-3-(3-cyanophenyl)urea] was dissolved in of 4 M HCl in dioxane/MeOH 5:1. The solution was stirred overnight at rt then the solvent was removed in vacuo. The residue was washed with diethylether, dried in vacuo, dissolved in dry MeOH (or DMF) and reacted with 1.1 to 2 equivalents of piperidin-4-ol (or 1.1 to 2 equivalents of the corresponding secondary amine) at temperature between 55 and 70° C. for a minimum of 4 h to a maximum of 22 h. The products were purified either by flash chromatography, using a silica gel column and an appropriate gradient of MeOH in DCM as eluent, or by preparative HPLC, using a reverse-phase column and a gradient of acetonitrile in 0.1% HCOOHaq.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)[C:12]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:11]=3[N:10]=2)=[C:6]([OH:8])[CH:7]=1.[CH3:28][O:29][C:30](=[O:41])[CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39]Br)=[CH:35][CH:34]=1>>[CH3:28][O:29][C:30](=[O:41])[CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][O:8][C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[C:9]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)[C:12]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:11]=3[N:10]=2)=[CH:35][CH:34]=1
Reactant: Oc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1Cc1cccc(Cl)c1
Reactant: COC(=O)COc1ccc(CBr)cc1
Product: COC(=O)COc1ccc(COc2cc(Cl)ccc2-c2nc3cc(F)c(F)cc3n2Cc2cccc(Cl)c2)cc1

Procedure:
The title compound was prepared in analogy to Example 5, intermediate a, from 5-chloro-2-[1-(3-chloro-benzyl)-5,6-difluoro-1H-benzoimidazol-2-yl]-phenol (Example 53, intermediate a) and (4-bromomethyl-phenoxy)-acetic acid methyl ester (CAS Reg. No. 104508-23-8). Brown sticky solid (74%). MS (Turbo Spray): m/z=583.4 (M+H).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:18])[CH:14]=2)[C@H:9]1[C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[O:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=O)(C)(C)C>CCO.Cl.O1CCOCC1>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][O:26][C:20]1[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:19]=1[C@@H:9]1[C:10]2[C:15](=[CH:14][C:13]([F:18])=[CH:12][CH:11]=2)[CH2:16][CH2:17][NH:8]1)[CH3:32]
Reactant: CCOC(=O)COc1ccc(Cl)cc1[C@@H]1c2ccc(F)cc2CCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)COc1ccc(Cl)cc1[C@H]1NCCc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To an ice-cooled solution of (S)-1-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (640 mg, 1.38 mmol, 1 eq.) in EtOH (2.5 mL), 4M HCl in dioxane (5.5 mL) was added. The resulting solution was stirred at r.t. for 3 hours. The reaction mixture was concentrated in vacuo. The residue was partitioned between AcOEt and a sat. aq. NaHCO3 soln. The layers were separated and the aq. phase was extracted with AcOEt. The comb. org. phases were concentrated in vacuo to give the free amine.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1F.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:24]3[C:23]([Cl:22])=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:29])=[C:16]([Cl:21])[CH:15]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1c(Cl)cccc1Cl
Reactant: Oc1ccc(C2CN(Cc3ccccc3)CCO2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Clc1cc(C2CN(Cc3ccccc3)CCO2)ccc1Oc1c(Cl)cccc1Cl
Temperature: 25 °C
Yield: 50 %

Procedure:
A solution of 4-(4-benzyl-morpholin-2-yl)-2-chloro-phenol (0.50 g; 1.56 mmol), 2,6-dichlorofluorobenzene (0.26 g; 1.56 mmol) and K2CO3 (0.32 g; 2.35 mmol) in DMF (10 mL) was heated at 100° C. for three days. After cooling to RT, the mixture was diluted with EtOAc and washed with water (3×). The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, CH2Cl2/MeOH 99.5:0.5) to afford 4-Benzyl-2-[3-chloro-4-(2,6-dichloro-phenoxy)-phenyl]-morpholine (0.35 g).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][N:33]=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][N:7]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:8]3)=[CH:22][CH:23]=2)=[O:37])=[CH:34][N:33]=1
Reactant: Cc1ccc(C(=O)Cl)cn1
Reactant: CCOC(=O)Cc1nn(Cc2ccc(N)cc2)c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cc1nn(Cc2ccc(NC(=O)c3ccc(C)nc3)cc2)c2ccccc12
Yield: 72.5 %

Procedure:
Ethyl 2-[1-(4-aminobenzyl)-1H-indazol-3-yl]acetate (258 mg, 0.83 mmol) and triethylamine (0.4 mL, 2.87 mmol) were dissolved in dichloromethane (15 mL), and in an ice bath, dichloromethane solution (10 mL) of the prepared 6-methylnicotinoyl chloride (about 1.00 mmol) was added dropwise slowly. Upon completion of the dropwise addition, it was reacted at room temperature for 16 hours. An aqueous solution of sodium bicarbonate was added to quench, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduce pressure, and chromatographed on a silica gel column (petroleum ether:ethyl acetate=2:1) to obtain a white solid 258 mg, at a yield of 72.3%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]1[CH2:20][C:11]2[NH:12][C:13]3[CH:14]=[CH:15][C:16](Br)=[CH:17][C:18]=3[C:10]=2[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:22][N:23](C=O)C>[C-]#N.[Zn+2].[C-]#N.C([O-])(=O)C.[Zn+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Pd](Cl)Cl.[Zn]>[C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]1[CH2:20][C:11]2[NH:12][C:13]3[CH:14]=[CH:15][C:16]([C:22]#[N:23])=[CH:17][C:18]=3[C:10]=2[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H]1Cc2[nH]c3ccc(Br)cc3c2C1
Reactant: CN(C)C=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Product: CC(C)(C)OC(=O)N[C@@H]1Cc2[nH]c3ccc(C#N)cc3c2C1
Yield: 69 %

Procedure:
The following reagents are stirred together in DMF (250 mL) at 100° C. for 18 h: ((S)-7-bromo-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-carbamic acid tert-butyl ester (50.0 g, 142 mmol), zinc cyanide (11.9 g, 99.7 mmol), zinc acetate (5.22 g, 28.5 mmol), 1,1′-bis(diphenylphosphino)ferrocene)palladium (II) chloride (Pd(dppf)2Cl2) (1.74 g, 2.14 mmol), and zinc (3.72 g, 56.9 mmol). The reaction is concentrated to dryness and partitioned between water and ethyl acetate. The organics are washed with water and brine, then concentrated to afford a solid. The solid is chromatographed in two equal portions on silica gel (1600 mL) as follows: load as a solution in CH2Cl2 and elute with 2% EtOAc in CH2Cl2 (3 L), then 5% EtOAc in CH2Cl2. The product is recovered from the two columns to give 29 g (69%) of the title compound as a white solid. 1H-NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 7.74 (s, 1H), 7.34 (d, J=1.8 Hz, 2H), 5.05-4.96 (m, 2H), 3.37-3.25 (m, 2H), 2.80-2.63 (m, 2H), 1.46 (s, 9H).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:44])=[N:14][C:15]([CH3:43])=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([F:41])=[C:37]([CH3:42])[CH:36]=3)=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>CCO.O>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:44])=[N:14][C:15]([CH3:43])=[C:16]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([F:41])=[C:37]([CH3:42])[CH:36]=3)=[CH:30][CH:31]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(OCCc3ccc(F)c(C)c3)cc2)c1N1CCC(C)(C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(CCOc2ccc(-c3c(C)nc(C)c([C@H](OC(C)(C)C)C(=O)O)c3N3CCC(C)(C)CC3)cc2)ccc1F
Yield: 89.7 %

Procedure:
A mixture of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-(4-fluoro-3-methylphenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate (0.035 g, 0.058 mmol) and LiOH (0.014 g, 0.579 mmol) in 9:1 EtOH/H2O (2 mL) was refluxed for 3 h. Then, cooled and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-(4-fluoro-3-methylphenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetic acid (0.0298 g, 0.052 mmol, 89% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ 7.12-7.17 (m, 2H), 7.04-7.12 (m, 2H), 6.95-7.01 (m, 3H), 5.96 (br. s., 1H), 4.16-4.28 (m, 2H), 3.60 (br. s., 1H), 3.09 (t, J=7.0 Hz, 2H), 2.80-3.01 (m, 1H), 2.66 (s, 3H), 2.30 (d, J=1.7 Hz, 3H), 2.19-2.32 (m, 1H), 2.22 (s, 3H), 1.97-2.15 (m, 1H), 1.25 (s, 9H), 0.87 (br. s., 3H), 0.68 (br. s., 3H). 4H of piperidine were not resolved. LCMS (M+H)=577.3.
Reaction SMILES: COC1C=C(NC2C3N(N=CN=3)C(C3C=NNC=3)=CN=2)C=CC=1C(NCC1C=NC(C)=CC=1)=O.Br[C:36]1[N:41]2[N:42]=[CH:43][N:44]=[C:40]2[C:39]([NH:45][C:46]2[CH:47]=[CH:48][C:49]([NH:52][C:53](=[O:61])[CH2:54][C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)=[N:50][CH:51]=2)=[N:38][CH:37]=1.[NH2:62][C:63]([C:65]1[S:66][CH:67]=[C:68](B(O)O)[CH:69]=1)=[O:64]>>[C:55]1([CH2:54][C:53]([NH:52][C:49]2[N:50]=[CH:51][C:46]([NH:45][C:39]3[C:40]4[N:41]([N:42]=[CH:43][N:44]=4)[C:36]([C:68]4[CH:69]=[C:65]([C:63]([NH2:62])=[O:64])[S:66][CH:67]=4)=[CH:37][N:38]=3)=[CH:47][CH:48]=2)=[O:61])[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: O=C(Cc1ccccc1)Nc1ccc(Nc2ncc(Br)n3ncnc23)cn1
Reactant: NC(=O)c1cc(B(O)O)cs1
Agent: COc1cc(Nc2ncc(-c3cn[nH]c3)n3ncnc23)ccc1C(=O)NCc1ccc(C)nc1
Product: NC(=O)c1cc(-c2cnc(Nc3ccc(NC(=O)Cc4ccccc4)nc3)c3ncnn23)cs1

Procedure:
This compound may be prepared using methods as described for Compound 120, step 4, using N-[5-(5-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino)-pyridin-2-yl]-2-phenylacetamide and 2-(aminocarbonyl)thiophene-4-boronic acid. LCMS: Rt 1.06 min (100%) m/z (ESI) 471 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:14])[C:9]2[S:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21](Cl)=[O:22].N1C=CC=CC=1>ClC(Cl)C>[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([NH:1][C:2]1[C:7]([C:8](=[O:14])[C:9]2[S:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1)=[O:22]
Reactant: Nc1ncccc1C(=O)c1cccs1
Reactant: O=C(Cl)CCCCCBr
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: O=C(CCCCCBr)Nc1ncccc1C(=O)c1cccs1

Procedure:
2-Amino-3-(2-thenoyl)pyridine is reacted with 6-bromohexanoyl chloride in the presence of pyridine in dichloroethane to give 2-(6-bromohexanoylamino)-3-(2-thenoyl)pyridine.
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:5][CH:4]=1)=O.[Na].[CH2:13]([NH:16][OH:17])[CH2:14][CH3:15]>>[CH2:13]([N+:16]([O-:17])=[CH:1][C:3]1[O:7][C:6]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:5][CH:4]=1)[CH2:14][CH3:15]
Reactant: O=Cc1ccc(S(=O)(=O)O)o1
Reactant: CCCNO
Agent: [Na]
Product: CCC[N+]([O-])=Cc1ccc(S(=O)(=O)O)o1
Yield: 41 %

Procedure:
Following the procedure of Example 1 above and using 5-formylfuran-2-sulfonic acid, sodium salt hydrate and N-propylhydroxylamine, the title compound was prepared in 41% yield as the sodium salt, m.p. 230-233° C. (dec.).
Reaction SMILES: [Cl-].[CH3:2][C:3]1[S:32][C:6]2=[N:7][C:8]([CH2:12][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:9][C:10](=[O:11])[N:5]2[CH:4]=1.[H-].[Na+].[CH:35]1([CH2:38][O:39][C:40]2[C:47]([O:48][CH3:49])=[CH:46][CH:45]=[CH:44][C:41]=2[CH:42]=O)[CH2:37][CH2:36]1>CS(C)=O>[CH:35]1([CH2:38][O:39][C:40]2[C:47]([O:48][CH3:49])=[CH:46][CH:45]=[CH:44][C:41]=2/[CH:42]=[CH:12]/[C:8]2[N:7]=[C:6]3[S:32][C:3]([CH3:2])=[CH:4][N:5]3[C:10](=[O:11])[CH:9]=2)[CH2:36][CH2:37]1
Reactant: Cc1cn2c(=O)cc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc2s1
Reactant: COc1cccc(C=O)c1OCC1CC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cccc(/C=C/c2cc(=O)n3cc(C)sc3n2)c1OCC1CC1

Procedure:
A stirred suspension of Step 2 intermediate (1.0 g, 2.096 mmol) in dry DMSO (12 ml) was treated with NaH (92 mg, 2.306 mmol) and 2-(cyclopropylmethoxy)-3-methoxybenzaldehyde (475 mg, 2.306 mmol) according to the procedure described in Step 3, Intermediate 2 to yield a crude solid which was purified by column chromatography using 2% ethyl acetate in DCM to afford the 600 mg of the desired compound as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.31-0.32 (m, 2H), 0.53-0.55 (m, 2H), 0.84-0.86 (s, 1H), 2.42 (s, 1H), 3.74-3.76 (m, 2H), 3.79 (s, 3H), 6.25 (s, 1H), 7.00-7.16 (m, 2H), 7.31-7.33 (m, 1H), 7.80 (s, 1H), 8.06-8.11 (m, 1H); ESI-MS (m/z) 369.24 (M+H)+.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[OH-].[Na+].[C:9]([O-:14])(=[O:13])[CH:10]([CH3:12])[OH:11].[S:15]([O-:19])([O-:18])(=[O:17])=[O:16].[Zn+2:20]>O>[C:1]([O-:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[Zn:20].[C:9]([O-:14])(=[O:13])[CH:10]([CH3:12])[OH:11].[S:15]([O-:19])([O-:18])(=[O:17])=[O:16].[Zn+2:20]
Reactant: CC(O)C(=O)O
Agent: CC(O)C(=O)[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: [Zn]

Procedure:
This lactate-zinc sulate buffer solution is prepared by first dissolving 2.12g of an 85 percent solution of lactic acid in 500 ml of distilled water and adjusting the pH to 3.5 with 0.1N sodium hydroxide. This solution is then further diluted to give a total volume of one liter. A 100 ml aliquot of the lactate solution is mixed with 100 ml of a 0.1 M zinc sulfate solution and this mixture diluted to one liter to provide the final lactate-zinc sulfate buffer solution.