Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4](=[O:15])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:7]=1[C:13]#[N:14])C.[CH:16]([NH:18]N)=O.O.C[N:22]1C(=O)CCC1>>[Br:12][C:9]1[CH:10]=[CH:11][C:6]2[NH:5][C:4](=[O:15])[N:14]3[N:22]=[CH:16][N:18]=[C:13]3[C:7]=2[CH:8]=1
Reactant: CCOC(=O)Nc1ccc(Br)cc1C#N
Reactant: CN1CCCC1=O
Reactant: NNC=O
Solvent: O
Product: O=c1[nH]c2ccc(Br)cc2c2ncnn12
Temperature: 160 °C
Reaction time: 1.5 h
Yield: 81 %

Procedure:
To a solution of (4-bromo-2-cyano-phenyl)-carbamic acid ethyl ester (40.4 g, 150 mmol) in NMP (170 mL) was added formylhydrazine (10.0 g, 150 mmol). The resulting mixture was stirred for 1.5 h at 160° C. under a gentle nitrogen sweep. It was cooled to below 100° C. and water (340 mL) was added slowly. The resulting slurry was cooled to 25° C. and stirred for 15 min. The solid was collected by filtration and washed with water and 2-propanol. Drying in vacuo afforded the title compound (32.4 g, 81%) as a light yellow solid. MS: m/e 264.9/267.0 [M+H+].
Reaction SMILES: O=[C:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:12]=1[C:13]#[N:14].Cl[Sn](Cl)(Cl)Cl>C1(C)C=CC=CC=1>[CH2:7]([O:6][C:4]([C:3]1[C:2]([CH3:9])=[N:10][C:11]2[C:12]([C:13]=1[NH2:14])=[C:15]([O:19][CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1)[CH:16]=[CH:17][CH:18]=2)=[O:5])[CH3:8]
Reactant: CCOC(=O)CC(C)=O
Reactant: N#Cc1c(N)cccc1OC1CCCCC1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C)nc2cccc(OC3CCCCC3)c2c1N
Temperature: 110 °C
Reaction time: 2.5 h
Yield: 85.1 %

Procedure:
A solution of ethyl 3-oxobutanoate (29.9 g, 0.230 mol) in anhydrous toluene (200 mL) was added to a solution of 2-amino-6-(cyclohexyloxy)benzonitrile (Example 36b, 49.8 g, 0.230 mol) in anhydrous toluene (1000 mL) under nitrogen in a 3 L round bottom flask sitting in an oil bath at room temperature. SnCl4 (53.9 mL, 0.461 mol) was added slowly over a period of approximately 1 h. The oil bath temperature was then raised to 110° C. and the reaction mixture was stirred at that temperature for 2.5 h. It was then cooled down to 5° C., still under nitrogen, and the toluene was decanted away from the immiscible viscous oil at the bottom of the flask. The viscous oil was further concentrated under vacuum at 60° C., re-dissolved in boiling ethyl acetate (1 L), and transferred to a 4 liter Erlenmeyer flask. The solution was diluted with more EtOAc (1.5 L), cooled down to −15° C., and neutralized with NaOH (3 N, 500 mL). The organic layer was separated, and the aqueous emulsion was extracted once more with ethyl acetate. The insoluble tin salts were filtered out from the aqueous layer, then both the salts and aqueous filtrate were washed once more with ethyl acetate. The combined organic layers were dried over MgSO4, concentrated, and passed through a silica column using 0% to 60% ethyl acetate in hexanes. The product was purified by recrystallization from EtOAc to give the title compound as an off-white solid (64.3 g, 85%). 1H NMR (400 MHz, DMSO-d6) δ 1.28-1.34 (m, 1H), 1.32 (t, 3H), 1.37-1.45 (m, 2H), 1.51-1.63 (m, 3H), 1.67-1.71 (m, 2H), 1.99-2.03 (m, 2H), 2.54 (s, 3H), 4.28-4.33 (q, J=6.8 Hz, 2H), 4.64 (m, 1H), 6.95-6.97 (d, J=7.6 Hz, 1H), 7.19-7.21 (d, J=8.4 Hz, 1H), 7.65 (t, J=8.4 Hz, 1H), 8.15 (brs, 2H). MS 329 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([C:6]#[N:7])=[C:4]([CH3:11])[N:3]=1.[C:12](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:13]>ClCCl>[N:1]([C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([C:6]#[N:7])=[C:4]([CH3:11])[N:3]=1)=[C:12]=[S:13]
Reactant: Cc1cc(N)nc(C)c1C#N
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: ClCCl
Product: Cc1cc(N=C=S)nc(C)c1C#N
Temperature: 40 °C
Reaction time: 3 h
Yield: 790 %

Procedure:
To 6-amino-2,4-dimethylnicotinonitrile (0.14 g, 0.95 mmol) in dichloromethane (20 mL) was added 1,1′-thiocarbonyldipyridin-2(1H)-one (0.23 g, 0.1 mmol). The reaction was stirred at 40° C. for 3 hours. The reaction was cooled to room temperature. The crude was purified by chromatography (Biotage: 25-100% ethyl acetate/hexane) to yield 6-isothiocyanato-2,4-dimethylnicotinonitrile (0.15 g, 0.79 mmol, 83% yield). 1H NMR (500 MHz, DMSO-D6) δ ppm 7.37 (s, 1 H), 2.63 (s, 3 H). MS (LC/MS) R.T.=2.40; [M+H]+=190.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=2)[CH:5]=[CH:4][CH:3]=1.[OH-].[K+].I[CH2:19][CH2:20][CH3:21]>CN(C)C=O>[CH3:1][C:2]1[N:7]=[C:6]([N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=2)[CH2:19][CH2:20][CH3:21])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(Nc2cccc(C)n2)n1
Reactant: CCCI
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCN(c1cccc(C)n1)c1cccc(C)n1
Reaction time: 1 h
Yield: 82.9 %

Procedure:
To a flask were added 1.0 g 6-methyl-N-(6-methylpyridin-2-yl)pyridin-2-amine, 0.84 g of pulverized potassium hydroxide and 15 ml of N,N-dimethylformamide. After stirring for 1 hour under nitrogen, the mixture was cooled to 5 C and 0.85 g of 1-iodopropane were added. The mixture was allowed to warm to 22 C and stirred for 16 hours. After quenching with 15 ml water, the product was extracted twice with diethyl ether and washed with water. Following removal of solvent, the product was purified by silica gel chromatography using 10% ethyl acetate in hexane to give 1.0 g of a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([Cl:16])[N:3]=1.[NH:17]1[CH2:22][CH2:21][CH:20]([N:23]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]2=[O:32])[CH2:19][CH2:18]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[ClH:16].[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[CH2:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:24]3=[O:32])[CH2:19][CH2:18]2)[N:3]=1
Reactant: O=C1c2ccccc2CN1C1CCNCC1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2nc(N3CCC(N4Cc5ccccc5C4=O)CC3)nc(N)c2cc1OC
Product: Cl

Procedure:
By heating in an analogous fashion 2.4 g of 4-amino-2-chloro-6,7-dimethoxyquinazoline, 2.2 g of 2-(4-piperidinyl)-isoindolin-1-one, 2.0 g of anhydrous sodium carbonate and 20 ml of dimethylformamide, the 2-[1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-piperidinyl]-isoindolin-1-one monohydrochloride is obtained, melting at 288°-289° (dec.).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]=[C:9]2[CH3:33])=[CH:4][CH:3]=1.Br[CH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O.O>[CH:35]1([O:1][C:2]2[CH:3]=[CH:4][C:5]([N:8]3[C:13](=[O:14])[C:12]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([C:22]5[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=5)=[CH:18][CH:17]=4)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]=[C:9]3[CH3:33])=[CH:6][CH:7]=2)[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: CCCc1nc(C)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc(OC3CCCC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 80 °C
Reaction time: 15 h
Yield: 90.8 %

Procedure:
To a solution of 4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.0 g) and bromocyclopentane (1.00 g) in N,N-dimethylformamide (10 mL) was added cesium carbonate (1.44 g), and the mixture was stirred at 80° C. for 15 hr. After allowing to cool, ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (1.05 g, 91%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20](=[O:31])[C:21]1[CH:26]=[C:25]([CH2:27]Br)[CH:24]=[CH:23][C:22]=1[O:29][CH3:30])[CH3:18]>>[CH2:17]([O:19][C:20](=[O:31])[C:21]1[CH:26]=[C:25]([CH2:27][N:14]2[CH2:15][CH2:16][CH:11]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[NH:8][CH:7]=3)[CH2:12][CH2:13]2)[CH:24]=[CH:23][C:22]=1[O:29][CH3:30])[CH3:18]
Reactant: CCOC(=O)c1cc(CBr)ccc1OC
Reactant: Fc1ccc2c(C3CCNCC3)c[nH]c2c1
Product: CCOC(=O)c1cc(CN2CCC(c3c[nH]c4cc(F)ccc34)CC2)ccc1OC
Yield: 100.8 %

Procedure:
This compound was prepared following the procedure described in example 1 (part D) starting with 0.5 g (2.2 mmol) of 6-fluoro-3-piperidin-4-yl-1H-indole and 0.8 g (2.9 mmol) of 5-bromomethyl-2-methoxy-benzoic acid ethyl ester. After standard purification, 0.91 g (100% of yield) of 5-[4-(6-fluoro-1H-indol-3-yl)-piperidin-1-ylmethyl]-2-methoxy-benzoic acid ethyl ester were obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10]Br.[CH2:13]([O:15][P:16]([O:20]CC)[O:17][CH2:18][CH3:19])[CH3:14]>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][P:16]([O:17][CH2:18][CH3:19])([O:15][CH2:13][CH3:14])=[O:20]
Reactant: COC(=O)c1ccccc1CBr
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1ccccc1C(=O)OC)OCC
Temperature: 150 °C
Reaction time: 16 h
Yield: 104.7 %

Procedure:
A mixture of 2-bromomethyl-benzoic acid methyl ester (5 g; 21.83 mmol; 1 eq.) and phosphorous acid triethyl ester (4.53 mL; 26.19 mmol; 1.2 eq.) was stirred at 150° C. for 16 hours then concentrated in vacuo to afford the title compound (6.54 g, quantitative) a yellow oil. HPLC (max plot) 88.8%; Rt 3.11 min.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]([O:13]C)=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][NH2:16]>>[C:1]1([S:7]([CH2:10][C:11]([NH:16][CH3:15])=[O:13])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CS(=O)(=O)c1ccccc1
Reactant: CN
Product: CNC(=O)CS(=O)(=O)c1ccccc1
Temperature: 25 °C

Procedure:
The entire isolated, crude and moist phenylsulfonylacetic acid methyl ester (V) was transferred to a 2-L Erlenmeyer flask and dissolved in 1 L (11.7 mol) of 40% aqueous methylamine. The reaction temperature rose to 30° C. The mixture was allowed to cool to ambient temperature, and was maintained at this temperature for an additional hour, followed by cooling overnight in a refrigerator. The precipitate product (IV) was removed by filtration. The filter cake was washed with 3×300 mL of cold water. Drying the recovered white solid at 60° C. at 30 torr over potassium hydroxide flakes for 27 h yielded 402.7 g of the methylacetamide (IV), 97.3% purity by HPLC, mp 106-109° C.
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH3:22][C:23]1[C:27](B(O)O)=[CH:26][N:25]([C:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:24]=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:9]2([C:6]3[CH:7]=[CH:8][C:3]([C:27]4[C:23]([CH3:22])=[N:24][N:25]([C:31]([C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=5)([C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=5)[C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)[CH:26]=4)=[CH:4][CH:5]=3)[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:16][CH:17]=1
Reactant: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1B(O)O
Reactant: Clc1ccc(C2(c3ccc(Br)cc3)CCNCC2)cc1
Agent: [Pd]
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc(C2(c3ccc(Cl)cc3)CCNCC2)cc1

Procedure:
4-(4-bromo-phenyl)-4-(4-chloro-phenyl)-piperidine hydrochloride was reacted with 3-methyl-1-trityl-1H-pyrazole-4-boronic acid* following the procedure set out in Example 1, but using tetrakis(triphenylphosphine) palladium (0) as the catalyst to give the title compound. LC/MS: (PS-B3) Rt 2.78 min [M+H]+ 594. * This starting material can be made by the method described in EP1382603
Reaction SMILES: ClC(OCC)=O.[CH:7]1([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.C(N(CC)CC)C.Cl.Cl.[NH2:25][C:26]1[CH:58]=[CH:57][C:29]([O:30][C:31]2[CH:32]=[CH:33][C:34]3[N:38]=[C:37]([CH2:39][O:40][C:41]4[CH:54]=[CH:53][C:44]([CH2:45][CH:46]5[S:50][C:49](=[O:51])[NH:48][C:47]5=[O:52])=[CH:43][CH:42]=4)[N:36]([CH3:55])[C:35]=3[CH:56]=2)=[CH:28][CH:27]=1>CN(C)C=O>[CH:7]1([C:13]([NH:25][C:26]2[CH:58]=[CH:57][C:29]([O:30][C:31]3[CH:32]=[CH:33][C:34]4[N:38]=[C:37]([CH2:39][O:40][C:41]5[CH:54]=[CH:53][C:44]([CH2:45][CH:46]6[S:50][C:49](=[O:51])[NH:48][C:47]6=[O:52])=[CH:43][CH:42]=5)[N:36]([CH3:55])[C:35]=4[CH:56]=3)=[CH:28][CH:27]=2)=[O:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(N)cc3)cc21
Reactant: O=C(O)C1CCCCC1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(NC(=O)C4CCCCC4)cc3)cc21
Reaction time: 1.5 h
Yield: 63.8 %

Procedure:
Ethyl chloroformate (87 mg) was added dropwise to a solution of cyclohexanecarboxylic acid (90 mg) and triethylamine (232 mg) in anhydrous N,N-dimethylformamide (8 ml) at ambient temperature. The mixture was stirred at the same temperature for 1.5 hours. To the reaction mixture was added 5-{4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazole-2-ylmethoxy]benzyl}thiazolidine-2,4-dione dihydrochloride (400 mg) in small portions. The mixture was stirred at 50° C. for 1.5 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated. On addition of ethyl acetate to the residue insoluble product was formed and isolated by filtration and washed with ethyl acetate to give the title compound (262 mg).
Reaction SMILES: [Cl-].[NH4+].[OH2:3].[CH3:4][N:5]([CH2:10][CH2:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=1)[S:6]([CH3:9])(=[O:8])=[O:7].C([OH:24])C>[Zn]>[S:6]([OH:8])([OH:24])(=[O:7])=[O:3].[NH2:19][C:16]1[CH:15]=[CH:14][C:13]([NH:12][CH2:11][CH2:10][N:5]([CH3:4])[S:6]([CH3:9])(=[O:8])=[O:7])=[CH:18][CH:17]=1
Reactant: CCO
Reactant: O
Reactant: CN(CCNc1ccc([N+](=O)[O-])cc1)S(C)(=O)=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Product: CN(CCNc1ccc(N)cc1)S(C)(=O)=O
Product: O=S(=O)(O)O

Procedure:
A mixture of zinc powder (25 g), ammonium chloride (1.1 g), water (11.2 mL), and 96% ethanol (67.5 mL) was brought to reflux in a boiling water bath. N-methyl-N-[2-(4-nitrophenylamino)ethyl]methanesulfonamide (23) (12.3 g, 0.045 mol) was added in portions and heating was continued until the reaction medium decolorized. The resulting mixture was filtered while boiling and the filtrate was recovered onto 3.8 mL of 96% sulfuric acid. The zinc was washed with ethanol, the filtrate was cooled in ice, and the precipitate that formed was filtered off by suction. After recrystallization from 30 mL of ethanol and 30 mL of water, 14.4 g of product were isolated. A second recrystallization from 45 mL of 50% ethanol gave 11.5 g of expected product having the following elemental analyses:
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C@@H:13]([NH:25][C:26]([C:28]1[S:29][C:30]([CH2:39][CH3:40])=[C:31]([C:33]2[N:37]([CH3:38])[N:36]=[CH:35][CH:34]=2)[CH:32]=1)=[O:27])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([F:24])([F:23])[F:22].NN>O1CCCC1.CO>[NH2:3][CH2:12][C@@H:13]([NH:25][C:26]([C:28]1[S:29][C:30]([CH2:39][CH3:40])=[C:31]([C:33]2[N:37]([CH3:38])[N:36]=[CH:35][CH:34]=2)[CH:32]=1)=[O:27])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([F:24])([F:23])[F:22]
Reactant: CCc1sc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1ccnn1C
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Product: CCc1sc(C(=O)N[C@H](CN)Cc2ccccc2C(F)(F)F)cc1-c1ccnn1C
Reaction time: 12 h
Yield: 57.1 %

Procedure:
To a solution of N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (486 mg, 0.86 mmol) in tetrahydrofuran (2.144 ml) and methanol (2.14 ml) at 25° C. was added hydrazine (0.269 ml, 8.58 mmol) dropwise. After 12 h, the solution was concentrated, dry loaded and purified via column chromatography (silica, 5% MeOH in DCM (1% NH4OH)). The free base was then converted to the HCl salt by adding excess 4M HCl in dioxane (500 ul) to the residue in MeOH (2 ml) affording N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (250 mg, 0.491 mmol, 57.2% yield)-2HCl as a white solid: LCMS (ES) m/z=437 (M+H)+, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.84 (d, J=8.84 Hz, 1H) 8.08 (br. s., 3H) 7.93 (s, 1H) 7.69 (d, J=7.83 Hz, 1H) 7.51-7.61 (m, 3H) 7.39-7.46 (m, 1H) 6.34 (d, J=2.02 Hz, 1H) 4.48 (br. s., 1H) 3.77 (s, 3H) 2.99-3.11 (m, 4H) 2.74 (q, J=7.49 Hz, 2H) 1.16 (t, J=7.45 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[CH2:11]([O:14][CH2:15][CH2:16]Br)[CH2:12]Br.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:16][CH2:15][O:14][CH2:11][CH2:12]2)[CH3:9])=[CH:4][CH:3]=1
Reactant: BrCCOCCBr
Reactant: C[C@H](N)c1ccc(Br)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](c1ccc(Br)cc1)N1CCOCC1
Yield: 58.9 %

Procedure:
(1S)-(−)-1-(4-Bromophenyl)ethylamine (2.4 g), 2,2′-dibromodiethylether (3.25 g) and N,N-diisopropylethylamine (6 ml) were heated to 100° C. in dimethylformamide (40 ml) for 18 h, allowed to cool and partitioned between water and ethyl acetate. The organic phase was dried (MgSO4), evaporated under vacuum and purified by column chromatography using a 0-40% ethyl acetate/iso-hexane gradient. The product was obtained as a yellow oil (1.91 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1B(O)O.Br[C:14]1[N:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)=[CH:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+].O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:14]1[N:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]2[CH2:23][CH2:24][N:25]([C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29])[CH2:26][CH2:27]2)=[CH:16][CH:15]=1
Reactant: CSc1ccc(B(O)O)c(F)c1
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)nc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CSc1ccc(-c2ccc(OCC3CCN(C(=O)OC(C)C)CC3)cn2)c(F)c1
Yield: 54.6 %

Procedure:
1-Methylethyl 4-[({6-[2-fluoro-4-(methylthio)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate (0.16 g, 55%) was prepared as a light yellow solid from [2-fluoro-4-(methylthio)phenyl]boronic acid (prepared as in Example 161, Alternative synthesis, Step 2, 0.26 g, 1.4 mmol), 1-methylethyl 4-{[(6-bromo-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate (prepared as in Example 81, Step 1, 0.25 g, 0.7 mmol), Na2CO3 (0.148 g, 1.4 mmol), Pd(PPh3)2Cl2 (49 mg, 0.07 mmol), water (1 mL) and DME (2 mL) in a manner similar to Example 21, Step 3. LRMS (APCI), m/z 419 (M+H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:14])=[C:9]([C:11]([OH:13])=O)[N:10]=2)[CH:7]=1.[CH3:15][N:16](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:17].F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.CNC>CN(C=O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:14])=[C:9]([C:11]([N:16]([CH3:17])[CH3:15])=[O:13])[N:10]=2)[CH:7]=1
Reactant: Cc1c(C(=O)O)nc2ccc(I)cn12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C(=O)N(C)C)nc2ccc(I)cn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
To a stirred solution of 6-iodo-3-methylimidazo[1,2-a]pyridine-2-carboxylic acid (150 mg) in DMF (5 ml) were added HATU (283 mg) and N,N-diisopropylethylamine (0.17 ml) at 0° C. The mixture was allowed to warm to room temperature and stirred for 30 min. Dimethylamine (2 M in THF, 0.2 ml) was added, and the resultant mixture was stirred at the same temperature for 18 h. The mixture was then concentrated in vacuo and the residue was diluted with DCM (100 ml). The DCM layer was successively washed with saturated aqueous NH4Cl solution (40 ml), saturated aqueous NaHCO3 solution (20 ml), water (30 ml) and brine (50 ml). The DCM layer was then dried m over Na2SO4, and concentrated in vacuo to give the title compound (150 mg) as a brown oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[C@H:11]([CH3:22])[O:10][C:9]1([CH3:24])[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:25]([O:27][C:28]1[N:29]=[CH:30][C:31]([C:34](O)=[O:35])=[N:32][CH:33]=1)[CH3:26].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:34]([C:31]3[CH:30]=[N:29][C:28]([O:27][CH2:25][CH3:26])=[CH:33][N:32]=3)=[O:35])=[CH:19][CH:20]=2)[C@H:11]([CH3:22])[O:10][C:9]1([CH3:23])[CH3:24])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cnc(C(=O)O)cn1
Reactant: C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CCc1ccc(N)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCOc1cnc(C(=O)Nc2ccc(CC[C@H]3[C@H](C)OC(C)(C)N3C(=O)OC(C)(C)C)cc2)cn1
Temperature: 50 °C
Reaction time: 8 h
Yield: 96.1 %

Procedure:
To a stirred solution of (4S,5S)-4-[2-(4-amino-phenyl)-ethyl]-2,2,5-trimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (120 mg) and 5-ethoxypyrazine-2-carboxylic acid (72.4 mg) in THF (3 ml) were added N-methylmorpholine (158 μl) and TBTU (230 mg). The reaction mixture was capped and shaken at 50° C. overnight. The crude reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (silica gel, gradient: 0% to 70% EtOAc in hexane) to afford (4S,5S)-4-(2-{4-[(5-ethoxy-pyrazine-2-carbonyl)-amino]-phenyl}-ethyl)-2,2,5-trimethyl-oxazolidine-3-carboxylic acid tert-butyl ester as a white solid (167 mg, 96%). MS (ISP): 507.3 ([M+Na]+), 502.3 ([M+NH4]+), 485.3 ([M+H]+), 429.3 ([M-C4H8]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=O.[OH-:14].[K+].C([O:18][C:19](=[O:24])[CH2:20][C:21]([CH3:23])=O)C.Cl>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:21]([CH3:23])[C:20]([C:19]([OH:24])=[O:18])=[C:6]2[C:7]([OH:12])=[O:14]
Reactant: CCOC(=O)CC(C)=O
Reactant: [OH-]
Reactant: COc1ccc2c(c1)C(=O)C(=O)N2
Agent: Cl
Agent: [K+]
Solvent: O
Product: COc1ccc2nc(C)c(C(=O)O)c(C(=O)O)c2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 59.4 g (0.335 mole) of 5-methoxyisatin, 225 g KOH in 800 ml H2O was treated dropwise with 121.4 g (0.932 mole) of ethylacetoacetate at 55° over a 2 hour period. The solution was refluxed 45 minutes and stirred 2 days at room temperature. Acidification with 300 ml concd. HCl while maintaining the temperature at ambient conditions gave a tan solid that was filtered, washed with H2O and dried; yield 60.8 g (69.4%).
Reaction SMILES: [ClH:1].O[C@H](COC1C=CC(C(C)(C)C)=CC=1)[CH2:4][NH:5]C(C)(C)CC1C=CC(OC)=CC=1.Cl.[OH:31][CH:32]([CH2:47][O:48][C:49]1[CH:54]=[CH:53][C:52](OC)=[CH:51][CH:50]=1)[CH2:33][NH:34][C:35]([CH3:46])([CH3:45])[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1>>[ClH:1].[OH:31][CH:32]([CH2:47][O:48][C:49]1[CH:50]=[CH:51][CH:52]=[C:53]([C:4]#[N:5])[CH:54]=1)[CH2:33][NH:34][C:35]([CH3:46])([CH3:45])[CH2:36][C:37]1[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=1
Reactant: COc1ccc(CC(C)(C)NC[C@H](O)COc2ccc(C(C)(C)C)cc2)cc1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(OC)cc2)cc1
Agent: Cl
Product: COc1ccc(CC(C)(C)NCC(O)COc2cccc(C#N)c2)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 339 (M−15, 0.1), 234 (15), 233 (100), 121 (21), 102 (7), 90 (6).