Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C-:1]#[N:2].[K+].C1(C)C=CC(S(O[CH2:14][C@H:15]2[CH2:23][C@@H:22]3[C@@H:18]([CH2:19][N:20]([C:24](=[O:35])[C@H:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[O:33][CH3:34])[CH3:26])[CH2:21]3)[C@@:17]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[F:43])([OH:36])[CH2:16]2)(=O)=O)=CC=1>CS(C)=O.ClCCl>[C:1]([CH2:14][C@@H:15]1[CH2:23][C@@H:22]2[C@@H:18]([CH2:19][N:20]([C:24](=[O:35])[C@H:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])[CH3:26])[CH2:21]2)[C@@:17]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[F:43])([OH:36])[CH2:16]1)#[N:2]
Reactant: [C-]#N
Reactant: COc1ccccc1[C@H](C)C(=O)N1C[C@@H]2C[C@H](COS(=O)(=O)c3ccc(C)cc3)C[C@@](O)(c3ccccc3F)[C@@H]2C1
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1ccccc1[C@H](C)C(=O)N1C[C@@H]2C[C@@H](CC#N)C[C@@](O)(c3ccccc3F)[C@@H]2C1
Temperature: 50 °C
Reaction time: 18 h
Yield: 149.6 %

Procedure:
0.35 g of potassium cyanide is added at room temperature to a solution of 1.55 g of (3aS,4S,6S,7aR)-6-p-toluenesulphonyloxymethyl-4-(2-fluorophenyl)-2-[(S)-2-(2-methoxyphenyl)propionyl]perhydroisoindol-4-ol in 15 cm3 of dimethyl sulphoxide. The reaction mixture is stirred at 50° C. for 18 hours and then diluted with 100 cm3 of dichloromethane, and the organic phase is washed with twice 50 cm3 of water then with 50 cm3 of saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). Recrystallization from diisopropyl ether gives 1.74 g of (3aS,4S,6S,7aR)-6-cyanomethyl-4-(2-fluorophenyl)-2-[(S)-2-(2-methoxyphenyl)propionyl]perhydroisoindol-4-ol in the form of white crystals melting at 182° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)=[CH:17][CH:16]=2)[CH:7]=1.[S:27]1[CH:31]=[CH:30][N:29]=[C:28]1[S:32](Cl)(=[O:34])=[O:33]>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)=[CH:17][CH:16]=2)[S:32]([C:28]2[S:27][CH:31]=[CH:30][N:29]=2)(=[O:34])=[O:33])[CH:7]=1
Reactant: O=S(=O)(Cl)c1nccs1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-n3cccn3)cc2)c1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-n3cccn3)cc2)S(=O)(=O)c2nccs2)c1

Procedure:
The title compound of Step A was prepared following the method described in Step A of Example 1 from 3-{3-[(4-pyrazol-1-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester, prepared in Step A of Example 11 h, and thiazole-2-sulfonyl chloride using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 7.95 (d, 1H), 7.88 (d, 1H), 7.69 (d, 1H), 7.60 (d, 1H), 7.54 (d, 2H), 7.19-7.12 (m, 3H), 7.04 (m, 1H), 6.93 (m, 2H), 6.44 (m, 1H), 4.49 (s, 2H), 4.46 (s, 2H), 3.64 (s, 3H), 2.82 (t, 2H), 2.51 (t, 2H); MS 497 (M+1).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)[N:19]2[CH2:23]CC[CH2:20]2)C2C=CC=CC=2N=N1.[C:34]([C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[NH:42][C:41](=[O:46])[CH2:40]2)(O)=[O:35].CNC.C(N(CC)CC)C>ClCCl>[CH3:20][N:19]([CH3:23])[C:34]([C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[NH:42][C:41](=[O:46])[CH2:40]2)=[O:35]
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: O=C1Cc2cc(C(=O)O)ccc2N1
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)c1ccc2c(c1)CC(=O)N2
Temperature: 25 °C
Reaction time: 3 h
Yield: 42 %

Procedure:
Benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP, 3.5 g, 6.72 mmol) was added to a mixture of 5-carboxy-2-oxindole (1 g, 5.6 mmol), dimethylamine (5.6 mL of 2.0 M in THF, 11.2 mmol) and triethylamine (2.0 mL, 14 mmol) in dichloromethane. After stirring at room temperature for 3 hours, the reaction was diluted with more dichloromethane, washed with water, saturated sodium bicarbonate and brine, dried and concentrated. The residue was purified by column chromatography to give 480 mg (42%) of 2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid dimethylamide.
Reaction SMILES: [F:1][C:2]1(F)[CH2:16][CH2:15][C:5]2([O:14][C:9]3=[N:10][CH:11]=[CH:12][CH:13]=[C:8]3[CH:7]=[CH:6]2)[CH2:4][CH2:3]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH2:16][CH2:15][C:5]2([O:14][C:9]3=[N:10][CH:11]=[CH:12][CH:13]=[C:8]3[CH:7]=[CH:6]2)[CH2:4][CH:3]=1
Reactant: FC1(F)CCC2(C=Cc3cccnc3O2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: FC1=CCC2(C=Cc3cccnc3O2)CC1
Temperature: 25 °C
Reaction time: 21 h
Yield: 42.6 %

Procedure:
4,4-Difluorospiro[cyclohexane-1,2′-pyrano[2,3-b]pyridine] (87) DAST (0.36 ml, 2.7 mmol) was added to a stirred ice-cooled solution of 4H-spiro[cyclohexane-1,2′-pyrano[2,3-b]pyridin]-4-one (85) (0.29 g, 1.3 mmol) in DCM (30 mL) under N2. The resulting mixture was allowed to warm up to rt and stirred at ambient temperature for 21 h. The mixture was poured into ice and saturated NaHCO3 aqueous solution and extracted with DCM (2×). The combined organics were washed with brine, dried over Na2SO4, and concentrated in vacuo to give a 2; 1 mixture of 4,4-difluorospiro[cyclohexane-1,2′-pyrano[2,3-b]pyridine] (87) and 4-fluorospiro[cyclohex-3-ene-1,2′-pyrano[2,3-b]pyridine] (88) (0.25 g, 80% yield). This material was taken onto the next step without separation. LCMS-ESI (POS), M/Z, M+1: Found 238.1.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][C@H:13]3[CH2:18][CH2:17][C@H:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[CH:8]=2)[CH:3]=1.[C:23]([Cu])#[N:24].O>CS(C)=O>[C:19]([C@H:16]1[CH2:15][CH2:14][C@H:13]([O:12][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[CH:3]=[C:2]([C:23]#[N:24])[CH:11]=[CH:10]3)[CH2:18][CH2:17]1)([CH3:20])([CH3:21])[CH3:22]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(Br)ccc3c2)CC1
Reactant: N#C[Cu]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C#N)ccc3c2)CC1
Temperature: 125 °C
Reaction time: 15 h

Procedure:
Compound 2-bromo-6-((trans)-4-tert-butylcyclohexyloxy)naphthalene (2.0 g, 5.55 mmol, 1.0 eq.) and CuCN (742 mg, 8.34 mmol, 1.5 eq.) was dissolved in DMSO (5 mL). Then the mixture was stirred at 125° C. for 15 h. Water was added and the mixture was extracted with ethyl acetate and the organic layer was purified by silica gel column chromatography using PE/EA (10/1) to give product as a slight yellow solid (1.423 g, 82%). EDI-MS (M+1)+: 308.0 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.78-7.73 (m, 2H), 7.54 (dd, 1H), 7.22 (dd, 1H), 7.14 (s, 1H), 4.33-4.30 (m, 1H), 2.29-2.25 (m, 2H), 1.93-1.90 (m, 2H), 1.48-1.26 (m, 2H), 1.25-1.10 (m, 3H), 0.91 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2].[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br>>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([O:15][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][Br:16])=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(O)ccc2o1
Reactant: BrCCCCCBr
Product: CCOC(=O)c1cc2cc(OCCCCCBr)ccc2o1
Yield: 73 %

Procedure:
Starting with 2.41 g (11.69 mmol) of 5-hydroxy-2-benzofuran-carboxylic acid ethyl ester, and 8.06 (35.06 mmol) of 1,5-dibromopentane, the title compound (3.03 g; 73%) was obtained as a white solid, mp 31° C., using the procedure of example 21.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[N:12][C:13]([O:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=3[F:38])=[N:14][C:15]=2[NH:17][CH2:18][C@@H:19]([O:21][C:22](=[O:29])[C@@H:23]([NH:27]C)[CH:24]([CH3:26])[CH3:25])[CH3:20])[N:10](OCCC[Si](C)(C)C)[N:9]=1.Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[N:12][C:13]([O:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=3[F:38])=[N:14][C:15]=2[NH:17][CH2:18][CH:19]([O:21][C:22](=[O:29])[CH:23]([NH2:27])[CH:24]([CH3:26])[CH3:25])[CH3:20])[NH:10][N:9]=1
Reactant: CN[C@H](C(=O)O[C@@H](C)CNc1nc(Oc2ccc(F)cc2F)nc2c1c(-c1ccccc1Cl)nn2OCCC[Si](C)(C)C)C(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(CNc1nc(Oc2ccc(F)cc2F)nc2[nH]nc(-c3ccccc3Cl)c12)OC(=O)C(N)C(C)C
Temperature: 80 °C
Yield: 66.9 %

Procedure:
A mixture of (S)-3-methyl-2-methylamino-butyric acid (S)-2-[3-(2-chloro-phenyl)-6-(2,4-difluoro-phenoxy)-1-(3-trimethylsilanyl-propoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-1-methyl-ethyl ester (15 mg, 0.0197 mmol), HCl (1 mL of 5N aqueous solution) and dioxane (1 mL) was heated to 80° C. for 30 minutes and then cooled to room temperature. The reaction mixture was made mildly basic by addition of saturated aqueous sodium bicarbonate solution, and the resulting precipitate was filtered, washed with water and dried under vacuum to afford 7 mg of 2-amino-3-methyl-butyric acid 2-[3-(2-chloro-phenyl)-6-(2,4-difluoro-phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-1-methyl-ethyl ester.
Reaction SMILES: N[C@H:2]([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[C:3]([OH:5])=O.[CH:13]1([NH:20][C:21]([NH2:23])=[S:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([NH:20][C:21]2[S:22][C@@H:2]([CH2:6][CH:7]3[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]3)[C:3](=[O:5])[N:23]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: N[C@H](CC1CCCCC1)C(=O)O
Reactant: NC(=S)NC1CCCCCC1
Product: O=C1N=C(NC2CCCCCC2)S[C@H]1CC1CCCCC1

Procedure:
Synthesis was performed from (2R)-2-amino-3-cyclohexylpropanoic acid and N-cycloheptylthiourea according to Method E and C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:13])[C:5]([Cl:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(OC(C)C)(C)C.COB(OC)OC.Br[C:29]([C:31]([F:34])([F:33])[F:32])=[CH2:30].C(=O)([O-])[O-].[K+].[K+]>CCCCCC.CCCCCC.C([Li])CCC.O1CCCC1.[Pd].C(C1C=CC=C(C(C)C)C=1N1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C1=C1CC(=O)C2C(=CC=CC=2)C1=O)(C)C.C(OCC)(=O)C.O>[Cl:13][C:4]1[CH:3]=[C:2]([C:29]([C:31]([F:34])([F:33])[F:32])=[CH2:30])[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]=1[Cl:12]
Reactant: C=C(Br)C(F)(F)F
Reactant: FC(F)(F)c1cc(Br)cc(Cl)c1Cl
Agent: [Pd]
Agent: CC(C)c1cccc(C(C)C)c1N1C=CN(c2c(C(C)C)cccc2C(C)C)C1=C1CC(=O)c2ccccc2C1=O
Agent: COB(OC)OC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: C=C(c1cc(Cl)c(Cl)c(C(F)(F)F)c1)C(F)(F)F
Temperature: -10 °C

Procedure:
In a nitrogen atmosphere, to a solution of 26.2 g of 5-bromo-2,3-dichlorobenzotrifluoride and 9.1 g of diisopropyl ether in 250 mL of hexane, 57.5 mL of an n-butyl lithium hexane solution (1.55 M) was gradually dropped while stirring the solution at −10° C. After the completion of the dropping, the resultant mixture was stirred at the same temperature for 30 minutes. Next, into the reaction mixture, a solution of 9.26 g of trimethoxyborane in 30 mL of tetrahydrofuran was dropped and the resultant mixture was continuously stirred at room temperature further for 10 minutes. To this reaction mixture, 150 mL of water, 23.4 g of 2-bromo-3,3,3-trifluoropropene, 36.9 g of potassium carbonate and 0.131 g of 1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene(1,4-naphthoquinone) palladium (0) dimer were added and the resultant mixture was stirred at 60° C. for 4 hours. After the completion of the reaction, the reaction mixture was left to be cooled down to room temperature, and 50 mL of ice water and 75 mL of ethyl acetate were added to the reaction mixture, followed by separating off the insoluble substance and by cleaning the insoluble substance with 75 mL of ethyl acetate. The organic phase of the filtrate was separated off and the resultant organic phase was washed with water and then dehydrated and dried over saturated saline and anhydrous sodium sulfate in this order. The solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography eluting with hexane to obtain 21.8 g of the objective substance as a colorless oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH2:12][CH2:13][NH2:14])[CH:6]=1)=[O:4].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:25][CH3:26])=[C:20]([CH:24]=1)[C:21](Cl)=[O:22]>ClCCl.N1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH2:12][CH2:13][NH:14][C:21](=[O:22])[C:20]2[CH:24]=[C:16]([Cl:15])[CH:17]=[CH:18][C:19]=2[O:25][CH3:26])[CH:6]=1)=[O:4]
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Reactant: COC(=O)c1ccc(=O)n(CCN)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(=O)n(CCNC(=O)c2cc(Cl)ccc2OC)c1

Procedure:
1-(2-aminoethyl)-1,6-dihydro-6-oxo-3-pyridinecarboxylic acid methyl ester (0.985 g, 5.0 mmol) was reacted with 5-chloro-2-methoxybenzoyl chloride (1.04 g, 5.1 mmol) in dichloromethane (25 ml) and pyridine (10 ml). After an aqueous work-up, purification via flash column chromotography (silica gel, 8% methanol/dichloromethane) gave the product, MP: 149°-150° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([F:17])[CH:16]=1)[CH2:5][NH:6][C:7](=[O:13])[CH:8]([CH3:12])[C:9]([OH:11])=[O:10].[CH2:18](C(C(OCC)=O)C(OCC)=O)C>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([F:17])[CH:16]=1)[CH2:5][NH:6][C:7](=[O:13])[CH:8]([CH2:12][CH3:18])[C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)C(CC)C(=O)OCC
Reactant: CC(C(=O)O)C(=O)NCc1cc(F)cc(F)c1
Product: CCC(C(=O)O)C(=O)NCc1cc(F)cc(F)c1

Procedure:
N-(3,5-Difluoro-benzyl)-2-ethyl-malonamic acid was prepared in analogy to N-(3,5-difluoro-benzyl)-2-methyl-malonamic acid (example 1) from diethyl ethyl-malonate.
Reaction SMILES: ClC1C=CC=C(F)C=1COC1N(C2C=CC=CC=2C(F)(F)F)C(SCC2C(F)=CC=CC=2Cl)=NN=1.[Cl:36][C:37]1[CH:38]=[C:39]([N:43]2[C:47]([S:48][CH2:49][C:50]3[CH:55]=[CH:54][C:53]([Cl:56])=[CH:52][C:51]=3[Cl:57])=[N:46][N:45]=[C:44]2[OH:58])[CH:40]=[CH:41][CH:42]=1.Br[CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[C:63]([F:67])[C:62]=1[F:68].C[O-].[Na+]>CN(C=O)C>[Cl:36][C:37]1[CH:38]=[C:39]([N:43]2[C:44]([O:58][CH2:60][C:61]3[CH:66]=[CH:65][CH:64]=[C:63]([F:67])[C:62]=3[F:68])=[N:45][N:46]=[C:47]2[S:48][CH2:49][C:50]2[CH:55]=[CH:54][C:53]([Cl:56])=[CH:52][C:51]=2[Cl:57])[CH:40]=[CH:41][CH:42]=1
Reactant: Fc1cccc(CBr)c1F
Reactant: Oc1nnc(SCc2ccc(Cl)cc2Cl)n1-c1cccc(Cl)c1
Agent: C[O-]
Agent: Fc1cccc(Cl)c1COc1nnc(SCc2c(F)cccc2Cl)n1-c1ccccc1C(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cccc(COc2nnc(SCc3ccc(Cl)cc3Cl)n2-c2cccc(Cl)c2)c1F

Procedure:
4-(3-chlorophenyl)-3-((2,4-dichlorobenzyl)thio)-5-((2,3-difluorobenzyl)oxy)-4H-1,2,4-triazole (599) was prepared in a similar manner as that described for the synthesis of compound 598 using 4-(3-chlorophenyl)-5-((2,4-dichlorobenzyl)thio)-4H-1,2,4-triazol-3-ol (50 mg, 0.129 mmol), 1-(bromomethyl)-2,3-difluorobenzene (40 mg, 0.194 mmol), sodium methoxide (17.4 mg, 0.322 mmol), and DMF (1.0 mL). 1H NMR (400 MHz, CDCl3) δ: 7.40-7.39 (m, 2H), 7.34-7.31 (m, 2H), 7.25-7.05 (m, 6H), 5.11 (s, 2H), 4.24 (s, 2H). LC-MS ESI m/z; found 512.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17](C)(C)[O:18][SiH2]C(C)(C)C)[CH:12]=2)[CH:10]=1)=[O:5])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][OH:18])[CH:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(-c2cccc(C(C)(C)O[SiH2]C(C)(C)C)c2)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(-c2cccc(CO)c2)cn1
Temperature: 70 °C
Yield: 78.3 %

Procedure:
To a solution of compound 6 (1.50 g, 4.2 mmol) in THF (18 mL) was added tetrabutylammonium fluoride (1.58 g, 5 mmol) and refluxed at 70° C. for 12 h. After concentration, the residue was purified by filter column using 4% methanol in chloroform to give alcohol 7 (810 mg, 79%) as pale yellow gum.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:11][CH:10]=[C:9]([C:12]([OH:14])=O)[CH:8]=2)=[CH:5][CH:4]=[N:3]1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:48][CH:49]([C:59]1[C:68]2[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=2)[CH:62]=[CH:61][CH:60]=1)[CH2:50][NH:51][C:52](=[O:58])[O:53][C:54]([CH3:57])([CH3:56])[CH3:55]>C(Cl)Cl>[CH3:1][N:2]1[C:6]([C:7]2[S:11][CH:10]=[C:9]([C:12]([NH:48][CH:49]([C:59]3[C:68]4[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=4)[CH:62]=[CH:61][CH:60]=3)[CH2:50][NH:51][C:52](=[O:58])[O:53][C:54]([CH3:57])([CH3:55])[CH3:56])=[O:14])[CH:8]=2)=[CH:5][CH:4]=[N:3]1
Reactant: CC(C)(C)OC(=O)NCC(N)c1cccc2ccccc12
Reactant: Cn1nccc1-c1cc(C(=O)O)cs1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nccc1-c1cc(C(=O)NC(CNC(=O)OC(C)(C)C)c2cccc3ccccc23)cs1
Reaction time: 16 h
Yield: 31.9 %

Procedure:
To a solution of 5-(1-methyl-1H-pyrazol-5-yl)-3-thiophenecarboxylic acid (104 mg, 0.5 mmol), PyBrOP (384 mg, 0.83 mmol) and diisopropylethyl amine (0.14 mL, 0.83 mmol) in DCM (8 mL) at 25° C. was added 1,1-dimethylethyl [2-amino-2-(1-naphthalenyl)ethyl]carbamate (144 mg, 0.5 mmol) [from Preparation 6]. After 16 h, the solution was partitioned between H2O and washed with DCM. The combined organic fractions were dried (Na2SO4), concentrated and purified via column chromatography (silica) affording the title compound (76 mg, 32%) as a white solid: LC-MS (ES) m/z=477 (M+H)+.
Reaction SMILES: C(OC(N1[CH2:13][CH2:12][N:11]([C:14](=[O:27])[CH2:15][CH2:16][C:17]2[C:25]3[C:24](=[O:26])[CH2:23][CH2:22][CH2:21][C:20]=3[NH:19][CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.N1CC[CH:31]([OH:34])CC1>>[OH:34][CH:31]1[CH2:9][CH2:10][N:11]([C:14](=[O:27])[CH2:15][CH2:16][C:17]2[C:25]3[C:24](=[O:26])[CH2:23][CH2:22][CH2:21][C:20]=3[NH:19][CH:18]=2)[CH2:12][CH2:13]1
Reactant: OC1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)CCc2c[nH]c3c2C(=O)CCC3)CC1
Product: O=C1CCCc2[nH]cc(CCC(=O)N3CCC(O)CC3)c21

Procedure:
3-[3-(4-Hydroxy-piperidin-1-yl)-3-oxo-propyl]-1,5,6,7-tetrahydro-indol-4-one was prepared by following the procedure described for the synthesis of 4-[3-(4-oxo-4,5,6,7-tetrahydro-1H-indol-3-yl)-propionyl]-piperazine-1-carboxylic acid tert-butyl ester (Step 1 of example 8) by substituting tert-butyl 1-piperazinecarboxylate with piperidin-4-ol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][N:15]=[N+]=[N-])([CH3:4])([CH3:3])[CH3:2].[C:19]([OH:24])(=[O:23])[C:20]([OH:22])=[O:21]>C(OC)(C)(C)C.[Pd]>[C:19]([OH:24])(=[O:23])[C:20]([OH:22])=[O:21].[NH2:15][CH2:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:18]
Reactant: CC(C)(C)OC(=O)Cc1ccccc1CN=[N+]=[N-]
Agent: [Pd]
Agent: O=C(O)C(=O)O
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)Cc1ccccc1CN
Reaction time: 2 h
Yield: 43.7 %

Procedure:
To a solution of 78.0 g (0.312 mol) 2-azidomethylphenylacetic acid t-butyl ester in 1.36 L TBF was added 7.8 g (50% water wet) 5% Pd on C and the mixture shaken mechanically in a 2 L heavy-walled flask under H2 at 45 psi for 2 h. The catalyst was removed by filtration through a bed of celite, rinsing with 250 mL THF. To the filtrate was added a solution of 31.25 g (0.347 mol) oxalic acid in 500 mL methyl tert-butyl ether, and the resultant suspension stirred at room temperature for 30 min. The solid was collected on a filter and washed with 300 mL methyl tert-butyl ether (the filtration was very slow, requiring about 3 hours). Drying under reduced pressure at 60° C. for 18 h gave 42.4 g (39% overall from 2-bromomethylphenylacetic acid) tert-butyl [2-(aminomethyl)phenyl]acetate oxalate salt as a white powder. The product is unstable as the free base, and will cyclize to the amide over several hours at room temperature.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[CH:22]=[N:23][N:24](COCC[Si](C)(C)C)[C:17]=23)[CH:12]=[CH:11][N:10]=1.FC1C=CC(F)=CC=1C1C=C(NC2C3C(=CN(COCC[Si](C)(C)C)N=3)N=CC=2)C=CN=1.[F:65][C:66]([F:71])([F:70])[C:67]([OH:69])=[O:68]>C1(OC)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[CH:22]=[N:23][NH:24][C:17]=23)[CH:12]=[CH:11][N:10]=1.[C:67]([OH:69])([C:66]([F:71])([F:70])[F:65])=[O:68]
Reactant: C[Si](C)(C)CCOCn1ncc2nccc(Nc3ccnc(-c4cc(F)ccc4F)c3)c21
Agent: C[Si](C)(C)CCOCn1cc2nccc(Nc3ccnc(-c4cc(F)ccc4F)c3)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Fc1ccc(F)c(-c2cc(Nc3ccnc4cn[nH]c34)ccn2)c1
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
A mixture of N-(2-(2,5-difluorophenyl)pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine and N-(2-(2,5-difluorophenyl)pyridin-4-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[4,3-b]pyridin-7-amine (1.2 g, 3.2 mmol) were combined with trifluoroacetic acid (1.1 mL) and stirred at 70° C. for 15 minutes. Anisole (20 μL) was then added and the mixture was further heated at 70° C. The reaction mixture was then purified via preparative HPLC using a gradient of 10-30% acetonitrile (containing 0.035% TFA) in water (containing 0.05% TFA) using a Sunfire Prep 5 μm C18, 75×30 mm column to give the title compound as a TFA salt. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.39-7.52 (m, 4H) 7.79 (br. s., 2H) 7.95 (s, 1H) 8.57 (d, J=6.32 Hz, 2H) 8.76 (br. s., 2H). MS [M+H] found 324.2.
Reaction SMILES: [C:1]1([CH2:11][C:12]([CH2:21][C:22]2[C:31]3[CH2:30][CH2:29][CH2:28][CH2:27][C:26]=3[CH:25]=[CH:24][CH:23]=2)(C(OC)=O)[C:13]([O:15]C)=[O:14])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>C(O)CCC.O>[C:1]1([CH2:11][CH:12]([CH2:21][C:22]2[C:31]3[CH2:30][CH2:29][CH2:28][CH2:27][C:26]=3[CH:25]=[CH:24][CH:23]=2)[C:13]([OH:15])=[O:14])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C(Cc1cccc2c1CCCC2)(Cc1cccc2c1CCCC2)C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCCCO
Product: O=C(O)C(Cc1cccc2c1CCCC2)Cc1cccc2c1CCCC2
Yield: 78.7 %

Procedure:
A solution of 3.1 g (7.4 mmol) of dimethyl bis-(5,6,7,8-tetrahydro-1-naphthylmethyl)-malonate in 20 mL n-butanol was treated with a solution of 1.24 g (22 mmol) of potassium hydroxide (KOH) in 20 mL H2O and the solution heated at reflux overnight. The solvent was removed under reduced pressure and the residue taken up in H2O and acidified with dilute HCl to the Congo red color change. The mixture was extracted with EtOAc and the EtOAc washed with 1N HCl, and then a saturated solution of NaCl. Drying over MgSO4 and removal of the solvent under reduced pressure gave 2.03 g of the product. A small amount recrystallized from EtOAc/hexane had mp 144-146° C. The structure was confirmed by NMR spectroscopy.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[CH:17]=[C:16]([C:18]4[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH:23]=4)[NH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1.C([N:38]1[CH:42]=[CH:41][CH:40]=[C:39]1B(O)O)(OC(C)(C)C)=O.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>O1CCOCC1.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]>[NH:38]1[CH:42]=[CH:41][CH:40]=[C:39]1[C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[CH:17]=[C:16]([C:18]4[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:22][CH:23]=4)[NH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Nc4cccc(I)c4)ncnc3[nH]2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Nc4cccc(-c5ccc[nH]5)c4)ncnc3[nH]2)CC1

Procedure:
To a stirred solution of tert-butyl 4-[4-(3-iodophenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (77.6 mg, 0.15 mmol), N-Boc-2-pyrrolylboronic acid (47.5 mg, 0.225 mmol) and potassium carbonate (41.5 mg, 0.3 mmol) in dioxane/water (4:1) (11.0 mL) was added PdCl2(dppf).CH2Cl2 (12.2 mg, 0.015 mmol). The mixture was heated at reflux for 18 h. Solvents were removed in vacuo and the residue was dissolved in DMF (≈2 mL). The DMF solution was filtered and purified by HPLC to afford the title compound. 1H-NMR(CD3OD, 400 MHz): δ=1.50 (s, 9H), 2.53 (m, 2H), 3.64 (m, 2H), 4.11 (m, 2H), 6.16 (t, J=2.8 Hz, 2H), 6.26 (s, 1H), 6.48 (dd, J=1.2, 3.6 Hz, 1H), 6.60 (s, 1H), 6.81 (dd, J=1.2, 2.8 Hz, 1H), 7.31 (s, 1H), 7.33 (s, 1H), 7.42-7.45 (m, 1H), 7.87 (s, 1H), 8.21 (s, 1H). MS (ES+): m/z 457.08 [MH+]. HPLC: tR=3.15 min (ZQ2000, polar—5 min).