Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[C:8]([OH:15])[C:7]=1[CH2:16][CH2:17][CH3:18].Br[CH2:20][C:21]([O:23][CH3:24])=[O:22].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:24][O:23][C:21](=[O:22])[CH2:20][O:15][C:8]1[C:9]([C:12](=[O:14])[CH3:13])=[CH:10][CH:11]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][Br:1])[C:7]=1[CH2:16][CH2:17][CH3:18]
Reactant: COC(=O)CBr
Reactant: CCCc1c(OCCCBr)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(OCCCBr)ccc(C(C)=O)c1OCC(=O)OC
Reaction time: 13 h
Yield: 58 %

Procedure:
A mixture of 5.0 g of 1-[4-(3-bromopropoxy)-2-hydroxy-3-propylphenyl]ethanone, 3.0 ml of methyl bromoacetate, and 3.3 g of anhydrous potassium carbonate in 75 ml of anhydrous acetone was stirred at reflux for 4 hours. An additional 2.0 g of potassium carbonate was added and reflux was continued for 13 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to an oil which was purified by high pressure liquid chromatography using 5% ethyl acetate-toluene to give 3.5 g (58%) of [6-acetyl-3-(3-bromopropoxy)-2-propylphenoxy]acetic acid methyl ester as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:10].[C:17]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:23]([C:20]2[CH:19]=[CH:18][C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)(=[O:25])=[O:24])=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])[CH:4]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccncc1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Product: O=C(c1ccncc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(-c2ccccc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 116 mg of (2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 126 mg of biphenyl-4-sulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 7.24 (m, 1H), 7.36 (m, 2H), 7.42 (m, 5H), 7.56 (m, 3H), 7.77-7.84 (m, 3H), 8.73 (d, 2H, J=4.4 Hz), 10.01 (s, 1H). MS: m/z 449.0 (M++1).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:15]2[N:14]=[C:13]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[N:12]([S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])[C:11]=2[CH:10]=[CH:9][CH:8]=1)(=O)=O.[Cl-].[Li+].[CH:36]([Sn](CCCC)(CCCC)CCCC)=[CH2:37]>O1CCCC1.[Pd].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>[CH:36]([C:7]1[C:15]2[N:14]=[C:13]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[N:12]([S:25]([C:28]([F:29])([F:31])[F:30])(=[O:27])=[O:26])[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[CH2:37]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=S(=O)(Oc1cccc2c1nc(COc1ccc(Cl)cc1)n2S(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=Cc1cccc2c1nc(COc1ccc(Cl)cc1)n2S(=O)(=O)C(F)(F)F
Reaction time: 5 h

Procedure:
In a 250 ml single neck round bottom flask, under a nitrogen atmosphere, were added 4-trifluoromethanesulfonyloxy-2-[(4-chlorophenoxy)methyl]-1-trifluoromethanesulfonylbenzimidazole (5.00 g, 9.28 mmol), lithium chloride (1.18 g, 27.84 mmol), vinyltributyltin (4.12 g, 12.99 mmol), and bis(triphenylphosphine)palladium(II) chloride (303 mg, 0.371 mmol) in anhydrous tetrahydrofuran (99 ml). The resulting mixture was stirred for five hours at reflux, followed by the addition of an additional 0.15 mg of the palladium catalyst. The contents were then stirred overnight. The progress of the reaction was monitored by thin layer chromatography. An additional 0.15 mg of the palladium catalyst and 0.5 ml of vinyltributyltin were added to the reaction mixture and it was refluxed for five hours. The desired title product was further purified by flash chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[C:7](=[O:14])[C:6]([C:15](OCC)=[O:16])=[C:5]2[OH:20].Cl.[CH3:22][O:23][C:24](=[O:27])[CH2:25][NH2:26].CN1CCCC1=O>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:12])([CH3:13])[C:7](=[O:14])[C:6]([C:15]([NH:26][CH2:25][C:24]([O:23][CH3:22])=[O:27])=[O:16])=[C:5]2[OH:20]
Reactant: CCOC(=O)C1=C(O)c2cc(Cl)ccc2C(C)(C)C1=O
Reactant: COC(=O)CN
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)CNC(=O)C1=C(O)c2cc(Cl)ccc2C(C)(C)C1=O
Temperature: 80 °C

Procedure:
A mixture of ethyl 6-chloro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalene-3-carboxylate (0.224 g, 0.761 mmol), glycine methyl ester hydrochloride (0.115 g, 0.914 mmol, 99% Aldrich), 1-methyl-2-pyrrolidinone (1.5 mL), and TEA (0.32 mL, 2.28 mmol) was heated at 80° C. for 4 hours. The resulting mixture was cooled to room temperature and treated with water (10 mL) causing a white solid to precipitate. The product was collected by vacuum filtration and rinsed with water. MS m/e=338.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[NH2:27][C:28]1[CH:32]=[CH:31][N:30]([CH2:33][C:34]([CH3:37])([OH:36])[CH3:35])[N:29]=1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:20][CH2:19][CH2:18]2)[C:13]([NH:27][C:28]2[CH:32]=[CH:31][N:30]([CH2:33][C:34]([OH:36])([CH3:35])[CH3:37])[N:29]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCC2)C(=O)O)cc1Cl
Reactant: CC(C)(O)Cn1ccc(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Product: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.3 %

Procedure:
In a flask (R)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclobutyl-propionic acid (85 mg, 0.27 mmol) was dissolved in methylene chloride (2 mL) and N,N-dimethylformamide (two drops) at 25° C. under argon. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 140 μL, 0.28 mmol) which produced gas evolution and it was then stirred at 25° C. for 30 minutes after which time it was concentrated in vacuo. The residue was then dissolved in methylene chloride (2 mL) and added dropwise into a solution of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared as in Example 80, 42 mg, 0.27 mmol), 2,6-lutidine (63 μL, 0.54 mmol) and methylene chloride (2 mL) at 0° C. It was then allowed to warm to 25° C. and stirred for 1.5 h. After this time, the reaction was quenched with a small amount of methanol and diluted with ethyl acetate (20 mL). This was then washed with a 1 N aqueous hydrochloric acid solution (10 mL) and a saturated aqueous brine solution (10 mL). It was then dried over sodium sulfate, filtered and concentrated with silica gel (2 g) in vacuo and then purified on Biotage Flash chromatography system (40S column, silica gel, 100% ethyl acetate/hexanes to 10% methanol/ethyl acetate) to afford (R)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclobutyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (80 mg, 66%) as a white foam: ES-HRMS m/e calcd for C21H28N3O4SCl (M+H)+ 454.1562, observed 454.1557; 1H NMR (300 MHz, DMSO-d6) δ 1.03 (s, 3H, CH3), 1.04 (s, 3H, CH3), 1.49-2.21 (m, 9H, CH and 4×CH2), 3.33 (s, 3H, SO2CH3), 3.79 (m, 1H, ArCHCO), 3.87 (s, 2H, NCH2), 4.65 (s, 1H, OH), 6.44 (d, J=2.2 Hz, 1H, Ar), 7.51 (d, J=2.2 Hz, 1H, Ar), 7.57 (dd, Jm=1.5 Hz, Jo=8.2 Hz, 1H, Ar), 7.67 (d, Jm=1.5 Hz, 1H, Ar), 8.00 (d, Jo=8.2 Hz, 1H, Ar), 10.76 (s, 1H, NH).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:24])[C:11]3[N:16]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)[N:15]=[C:14]([CH3:23])[C:12]=3[N:13]=2)=[C:4]([O:25][CH2:26][CH3:27])[CH:3]=1.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH:17]1([N:16]2[C:11]3[C:10](=[O:24])[NH:9][C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)=[CH:3][C:4]=4[O:25][CH2:26][CH3:27])=[N:13][C:12]=3[C:14]([CH3:23])=[N:15]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCOc1cc(Br)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Reactant: C1CNCCN1
Product: CCOc1cc(N2CCNCC2)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Yield: 57 %

Procedure:
The same reaction procedure as in Example 16 was performed, except that the compound obtained in Example 116 was used in place of the compound obtained in Example 15, and piperazine was used in place of N-methylpiperazine. In this manner, 86 mg (57%) of the captioned compound was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.[CH2:9]([OH:12])[C:10]#[CH:11]>C(N)CC.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.[Cu]I>[OH:12][CH2:9][C:10]#[C:11][C:2]1[CH:7]=[CH:6][C:5]([C:11]#[C:10][CH2:9][OH:12])=[CH:4][CH:3]=1
Reactant: C#CCO
Reactant: Brc1ccc(Br)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCN
Product: OCC#Cc1ccc(C#CCO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
A solution of 1,4-dibromobenzene (1.18 g, 5.0 mmol) in n-propylamine (15 ml) is admixed successively with Pd(Ph3P)4 (116 mg, 2%), CuI (28 mg, 3%) and propargyl alcohol (0.9 ml, 15 mmol) and stirred at RT for 1 h and then at reflux for 7 h. More Pd(Ph3P)4 (58 mg, 1%), CuI (14 mg, 1.5%) and propargyl alcohol (0.45 ml, 7.5 mmol) are then added, and the mixture is stirred at reflux for a further 8 h. After cooling, the reaction mixture is filtered off with suction over kieselguhr and the filter cake is washed with ethyl acetate (20 ml). The organic phase is concentrated under reduced pressure. Further purification is carried out by chromatography [Tol/Ac (8:2)] over a silica gel column. This gives the title compound (0.84 g) as a colorless solid. TLC, silica gel (glass plates), [toluene/acetone (8:2)], Rf=0.22.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:26]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.CO.[OH-].[Na+]>C1COCC1>[CH2:36]([O:35][C:32]1[CH:33]=[CH:34][C:29]([S:26]([C:6]2([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:14]=3)[CH2:10][CH2:11]2)(=[O:28])=[O:27])=[CH:30][CH:31]=1)[CH2:37][CH2:38][CH3:39]
Reactant: CCCCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3cccc(Oc4ccccc4)c3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3cccc(Oc4ccccc4)c3)CC2)cc1

Procedure:
4-(4-Butoxy-benzenesulfonyl)-1-(3-phenoxy-benzyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-butoxy-benzenesulfonyl)-1-(3-phenoxy-benzyl)-piperidine-4-carboxylic ethyl ester (10.7 g, 24 mmol) dissolved in THF:Methanol (75: 50 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 5.0 g (76%); off white solid; MS: 524.3 (M+H)+
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH:10]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:9][CH2:8]2)(=[O:3])[CH3:2].C([O-])(=O)C.[Na+].[Br:24]Br>C(O)(=O)C>[C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[Br:24])[CH:10]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: BrBr
Reactant: CC(=O)Nc1ccc2c(c1)CCC2CCC(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)Nc1cc2c(cc1Br)C(CCC(=O)O)CC2
Reaction time: 18 h

Procedure:
A solution of 5-acetamido-2-carboxyethylindane (18 g, 73 mmol), sodium acetate (9 g, 110 mmol) in acetic acid (300 mL) was treated dropwise with bromine (14.1 g, 88 mmol) and then stirred for 18 h. After removing the solvent, the residue was dissolved in an ether:water mixture, and sodium bisulfite was added. The ether layer was separated and the aqueous layer back extracted. The combined organic layers were washed with saturated NaCl, dried over magnesium sulfate, filtered and evaporated. The syrup was purified by silica gel chromatography (3:2 hexane:EtOAc) to give the product.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([F:15])([F:14])[F:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:16][CH3:17])[CH:8]=2)[N:3]=1.[C:18]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[C:23]([Cl:30])[CH:22]=1)([OH:20])=[O:19].C([O-])([O-])=O.[K+].[K+].Cl>COCCOCCO.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:30][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[C:2]1[C:11]([C:12]([F:15])([F:14])[F:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:16][CH3:17])[CH:8]=2)[N:3]=1)[C:18]([OH:20])=[O:19]
Reactant: O=C(O)c1ccc(B(O)O)c(Cl)c1
Reactant: COc1ccc2nc(Cl)c(C(F)(F)F)nc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: O
Solvent: COCCOCCO
Product: COc1ccc2nc(-c3ccc(C(=O)O)cc3Cl)c(C(F)(F)F)nc2c1
Temperature: 120 °C
Reaction time: 2 h
Yield: 68.6 %

Procedure:
A mixture of 2-chloro-6-methoxy-3-(trifluoromethyl)quinoxaline (Intermediate 11, 150 mg, 0.571 mmol), 4-carboxy-2-chlorophenylboronic acid (115 mg, 0.571 mmol), K2CO3 (160 mg, 1.14 mmol) and Pd(dppf)Cl2 (50 mg, 0.0612 mmol) in diethylene glycol monomethyl ether (2 mL) and water (0.6 mL) was stirred at 120° C. under N2 atmosphere for 2 hours. The resulting mixture was cooled to room temperature and diluted with water (50 mL), acidified with aqueous HCl (2M) until pH=5, extracted with EtOAc (50 mL×3), dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE/EtOAc=1/1) to give the product (150 mg, yield 68%) as a solid.
Reaction SMILES: S[C:2]1N=CN=C2C=1NC=N2.[NH2:11][C:12]1[N:20]=[C:19]2[C:15]([NH:16][CH:17]=[N:18]2)=[C:14]([SH:21])[N:13]=1>>[NH2:11][C:12]1[N:20]=[C:19]2[C:15]([NH:16][CH:17]=[N:18]2)=[C:14]([S:21][CH3:2])[N:13]=1
Reactant: Nc1nc(S)c2[nH]cnc2n1
Reactant: Sc1ncnc2nc[nH]c12
Product: CSc1nc(N)nc2nc[nH]c12

Procedure:
By repeating this procedure but replacing the above 6-mercaptopurine compound with the corresponding 2-amino-6-mercaptopurine compound there is obtained the corresponding 2-amino-6-methylthiopurine compound.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]([CH2:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1)[C:7]1[O:11][N:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=1)C.[H-].[Al+3].[H-].[H-].C(OCC)C.O>O1CCCC1>[C:19]1([CH2:18][N:6]([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=2)[CH2:5][CH2:4][OH:3])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)CN(Cc1cccc2ccccc12)c1cc(-c2ccccc2)no1
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCCN(Cc1cccc2ccccc12)c1cc(-c2ccccc2)no1
Yield: 65.9 %

Procedure:
[Naphthalen-1-ylmethyl-(3-phenyl-isoxazol-5-yl)-amino]-acetic acid ethyl ester (305 mg, 0.789 mmol) was dissolved in tetrahydrofuran (THF, 2 ml) and while stirring under argon, treated with a 1.0M ithium aluminum hydride in di ethyl ether solution (1.58 ml, 1.58 mmol) and stirred at rt for 1.5 hr. The reaction was diluted with THF (2 ml), followed by diethyl ether (10 ml), and water was added slowly dropwise to give a filterable solid. The mixture was filtered through super cel, the filter cake washed well with a THF/diethyl ether (1/4), and the filtrate stripped to dryness in vacuo to give a crude oil (200 mg). Flash chromatography on silica gel (10 to 15% diethyl ether in methylene chloride) gave the product as a white foam (179 mg, 65.9%).
Reaction SMILES: C([O-])=O.[NH4+].[C:5]([C:7]1[CH:8]=[C:9]([F:49])[C:10]([NH:21][CH:22]2[CH2:27][CH2:26][N:25](C(OCC3C=CC=CC=3)=O)[CH2:24][CH:23]2[N:38]2[C:46](=[O:47])[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39]2=[O:48])=[N:11][C:12]=1[NH:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([CH3:20])[CH:19]=1)#[N:6]>[Pd].C(OCC)(=O)C.CO>[O:48]=[C:39]1[C:40]2[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:46](=[O:47])[N:38]1[CH:23]1[CH:22]([NH:21][C:10]2[C:9]([F:49])=[CH:8][C:7]([C:5]#[N:6])=[C:12]([NH:13][C:14]3[CH:15]=[N:16][CH:17]=[C:18]([CH3:20])[CH:19]=3)[N:11]=2)[CH2:27][CH2:26][NH:25][CH2:24]1
Reactant: Cc1cncc(Nc2nc(NC3CCN(C(=O)OCc4ccccc4)CC3N3C(=O)c4ccccc4C3=O)c(F)cc2C#N)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cncc(Nc2nc(NC3CCNCC3N3C(=O)c4ccccc4C3=O)c(F)cc2C#N)c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 52.1 %

Procedure:
Ammonium formate (6 mg) and 10% Pd/C (6 mg) were added to an ethyl acetate/MeOH (1 ml/1 ml) solution containing benzyl 4-((5-cyano-3-fluoro-6-((5-methylpyridin-3-yl)amino)pyridin-2-yl)amino)-3-(1,3-dioxoisoindolin-2-yl)piperidin-1-carboxylate (37 mg) obtained in the 1st step in a nitrogen atmosphere, followed by heating and stirring at 70° C. for 1 hour. Next, ammonium formate (30 mg) and 10% Pd/C (30 mg) were added to the solution, followed by heating and stirring at 70° C. for 1 hour. The reaction solution was cooled to room temperature and insoluble matter was removed by filtration through Celite. Filter cake was washed with ethyl acetate. The resulting filtrate was mixed with wash liquid. The obtained organic layers were washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure. A white solid of 6-((3-(1,3-dioxoisoindolin-2-yl)piperidin-4-yl)amino)-5-fluoro-2-((5-methylpyridin-3-yl)amino)nicotinonitrile (15 mg) was thus obtained.
Reaction SMILES: Br[C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:5]([NH2:6])=[C:4]([O:12][CH3:13])[CH:3]=1.[CH3:14][N:15]1[CH2:20][CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH2:17][CH2:16]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.[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>[CH3:13][O:12][C:4]1[CH:3]=[C:2]([C:18]2[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH:17]=2)[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:5]=1[NH2:6]
Reactant: COc1cc(Br)c([N+](=O)[O-])cc1N
Reactant: CN1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(C2=CCN(C)CC2)c([N+](=O)[O-])cc1N
Yield: 92.3 %

Procedure:
A mixture of 4-bromo-2-methoxy-5-nitroaniline (Intermediate 4, 1.112 g, 4.5 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine (1.004 g, 4.50 mmol) and K2CO3 (2.488 g, 18.00 mmol) was stirred in 1,4-dioxane (20 mL) and water (5 mL). The mixture was purged with N2 for 0.25 h. Tetrakis(triphenylphosphine)-palladium(0) (0.052 g, 0.05 mmol) was then added and the mixture was heated at reflux for 2 h. The mixture was then cooled, filtered and the filtrate was concentrated in vacuo to give an aqueous mixture. This mixture was dissolved in EtOAc and water and the phases were separated. The aqueous solution was extracted with EtOAc. The combined organic solutions were then extracted twice with 2M HCl (40 mL). The aqueous solutions were basified with 2M Na2CO3 (50 mL) and extracted with EtOAc (3×40 mL). The combined organic solutions were dried (MgSO4) and concentrated in vacuo. The residue was dissolved in a mixture of CH2Cl2 and 2N methanolic ammonia (10:1, 10 mL) and the solution was filtered through a silica plug. The filtrate was concentrated in vacuo to give an oil which subsequently crystallised. Trituration with isohexane and diethyl ether (1:1, 5 mL) and collection of the resulting solid by filtration gave the title compound (1.093 g, 92%) as a yellow crystalline solid; 1H NMR: 2.23 (2H, dd), 2.27 (3H, s), 2.53 (2H, t), 2.93 (2H, d), 3.87 (3H, s), 5.27 (2H, s), 5.42-5.53 (1H, m), 6.65 (1H, s), 7.23 (1H, s); m/z: ES+ MH+ 264.
Reaction SMILES: O.[OH-].[Li+].[C:4]([O:8][C:9](=[O:34])[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH2:20][C@H:21]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:22]([O:24]C)=[O:23])=[CH:12]1)([CH3:7])([CH3:6])[CH3:5].Cl>O1CCOCC1.O>[C:4]([O:8][C:9](=[O:34])[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH2:20][C@H:21]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:22]([OH:24])=[O:23])=[CH:12]1)([CH3:6])([CH3:7])[CH3:5]
Reactant: COC(=O)[C@H](Cc1cn(CC(=O)OC(C)(C)C)c2ccccc12)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Cn1cc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
Lithium hydroxide monohydrate (0.455 g, 10.84 mmol) was added to a solution of (S)-methyl 3-(1-(2-(tert-butoxy)-2-oxoethyl)-1H-indol-3-yl)-2-((tert-butoxycarbonyl)amino)propanoate (4.69 g, 10.84 mmol) in dioxane (50 mL) and water (16.67 mL) and stirred at RT for 1 hr. The reaction was neutralized with 1M HCl and extracted with EtOAc. The organic layer washed with brine, collected, dried over MgSO4, filtered and evaporated to give the crude material. The crude material was purified via silica gel chromatography (120 g column, 0-50% EtOAc:Hex over 20 CV) to get the product (S)-3-(1-(2-(tert-butoxy)-2-oxoethyl)-1H-indol-3-yl)-2-((tert-butoxycarbonyl)amino)propanoic acid (3.54 g, 78% yield). 1H NMR (400 MHz, chloroform-d) d 7.62 (d, J=7.8 Hz, 1H), 7.26-7.21 (m, 2H), 7.15 (ddd, J=7.9, 5.6, 2.3 Hz, 1H), 6.99 (s, 1H), 5.08 (d, J=7.8 Hz, 1H), 4.71 (s, 2H), 4.65 (br. s., 1H), 3.42-3.31 (m, 2H), 1.46 (s, 18H). ESI-MS(+) m/z=441 (M+Na).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[CH2:21]([C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[C:26]([O:32][CH3:33])[CH:25]=1)[CH:22]=[CH2:23]>>[CH2:21]([C:24]1[CH:31]=[CH:30][C:27]([C:28]2[NH:1][C:2]3=[N:3][CH:4]=[C:5]([Cl:20])[C:6]([NH:9][C@@H:10]4[C@@H:15]5[CH2:16][C@@H:12]([CH:13]=[CH:14]5)[C@@H:11]4[C:17]([NH2:19])=[O:18])=[C:7]3[N:8]=2)=[C:26]([O:32][CH3:33])[CH:25]=1)[CH:22]=[CH2:23]
Reactant: C=CCc1ccc(C=O)c(OC)c1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Product: C=CCc1ccc(-c2nc3c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)c(Cl)cnc3[nH]2)c(OC)c1
Yield: 12 %

Procedure:
In a similar fashion as for the synthesis of III, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 4-allyl-2-methoxybenzaldehyde were reacted to produce the title compound as a yellow solid (12%). Mp. 123-6° C. 1H NMR (d-chloroform): 10.83 (br s, 1H), 8.32 (d, J=8 Hz, 1H), 8.02 (s, 1H), 7.00 (d, J=7 Hz, 1H), 6.91 (s, 1H), 6.46-6.31 (m, 3H), 6.00 (m, 1H), 5.55 (d, J=10 Hz, 1H), 5.28-5.12 (m, 4H), 4.05 (s, 3H), 3.48 (d, J=7 Hz, 1H), 3.18 (s, 1H), 2.91 (s, 1H), 2.87 (d. J=7 Hz, 1H), 2.35 (d, J=8 Hz, 1H), 1.75 (d, J=8 Hz, 1H). MS: 449.9 (M+H). HPLC retention time: 2.94 minutes (G Method).