Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:9][C@@H:8]2[C@@H:4]([N:5]([C:10]3[C:15]([N+:16]([O-])=O)=[CH:14][C:13]([NH:19][C:20]4[N:25]=[C:24]([C:26]5[CH:27]=[N:28][N:29]6[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=56)[CH:23]=[CH:22][N:21]=4)=[C:12]([O:35][CH3:36])[CH:11]=3)[CH2:6][CH2:7]2)[CH2:3]1.[NH4+].[Cl-].C(O)C>[Fe].O>[CH3:1][N:2]1[CH2:9][C@@H:8]2[C@@H:4]([N:5]([C:10]3[CH:11]=[C:12]([O:35][CH3:36])[C:13]([NH:19][C:20]4[N:25]=[C:24]([C:26]5[CH:27]=[N:28][N:29]6[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=56)[CH:23]=[CH:22][N:21]=4)=[CH:14][C:15]=3[NH2:16])[CH2:6][CH2:7]2)[CH2:3]1
Reactant: COc1cc(N2CC[C@@H]3CN(C)C[C@@H]32)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1cc(N2CC[C@@H]3CN(C)C[C@@H]32)c(N)cc1Nc1nccc(-c2cnn3ccccc23)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.2 %

Procedure:
A mixture of N-[4-[(3aR,6aR)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-1-yl]-2-methoxy-5-nitrophenyl]-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine (Intermediate 161, 190 mg, 0.39 mmol), iron (131 mg, 2.34 mmol), NH4Cl (14.62 mg, 0.27 mmol), ethanol (6 mL) and water (2 mL) was heated at reflux for 4 h and then stirred at r.t. overnight. Part-purification was achieved by ion exchange chromatography, using an SCX column and eluting with 7N methanolic ammonia. Appropriate fractions were then concentrated in vacuo onto silica. Purification by FCC, eluting with 0-5% 7N methanolic ammonia in CH2Cl2 provided impure material. The fractions containing desired product were combined and further purified by FCC, eluting with 0-2.5% 7N methanolic ammonia in CH2Cl2 to give the title compound (100 mg, 56%); m/z: ES+ MH+ 457.21.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][C:14]([C:16]2[O:17][C:18](Br)=[CH:19][CH:20]=2)=[O:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1>[N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][C:14]([C:16]2[O:17][C:18]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:20]=2)=[O:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccccc1
Reactant: O=C(Nc1ccccc1N1CCCCC1)c1ccc(Br)o1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccc1N1CCCCC1)c1ccc(Nc2ccccc2)o1
Temperature: 25 °C
Yield: 40 %

Procedure:
To a solution of 5-bromo-furan-2-carboxylic acid (2-piperidin-1-yl-phenyl)-amide (1.0 mmol) in toluene (7.5 mL) was added aniline (1.3 mmol), tris(dibenzylidineacetone)dipalladium(0) (“Pd2 dba”) (Aldrich) (0.05 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (“BINAP”) (0.1 mmol), and potassium tert-butoxide (“t-BuOK”) (1.5 mmol), and the resulting mixture was refluxed overnight. The reaction was then cooled to room temperature, passed through a plug of silica and concentrated. Purification of the dark brown residue by HPLC afforded the product. Yield: 40%. MS: 362 (M+1).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:30]=[CH:31][C:32]=2[F:33])[CH2:23][CH2:22]1>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[C:29]([NH:34][C:35](=[O:39])[CH:36]([CH3:37])[CH3:38])[CH:30]=[CH:31][C:32]=3[F:33])[CH2:23][CH2:22]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: CC(C)C(=O)Nc1ccc(F)c(C2CCN(CCCN)CC2)c1
Product: CC(C)C(=O)Nc1ccc(F)c(C2CCN(CCCNC(=O)C(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Example 24 was prepared from diphenylacetyl chloride and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-fluorophenyl}-2-methylpropanamide according to the procedures described in Scheme 8: 1H NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.47 (dd, 1H, J=2.4, 6.4 Hz), 7.34–7.21 (m, 11H), 7.06 (t, 1H, J=4.8 Hz), 6.91 (t, 1H, J=10.0 Hz), 4.90 (s, 1H), 3.38 (dd, 2H, J=6.0, 11.6 Hz), 2.90–2.87 (m, 2H), 2.74 (m, 1H), 2.50 (m, 1H), 2.36 (t, 2H, J=6.8 Hz), 1.96 (dt, 2H, J=2.8, 12.0 Hz), 1.73–1.62 (m, 6H), 1.20 (d, 6H, J=6.8 Hz); ESMS m/e: 516.3 (M+H)+.
Reaction SMILES: [CH:1]1C=CC2NC=C(CCO)C=2C=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:19]([O:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[C:30]2[C:36](=O)[C:37]([O:39][CH2:40][CH3:41])=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(C)=O>[CH2:19]([O:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31]1[C:40]([CH3:41])([CH3:1])[O:39][CH2:37][CH2:36][C:30]2=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)C(=O)c1c[nH]c2ccc(OCc3ccccc3)cc12
Reactant: OCCc1c[nH]c2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CC(C)=O
Product: CC1(C)OCCc2c1[nH]c1ccc(OCc3ccccc3)cc21

Procedure:
5-Benzyloxy-3-tryptophol (II; R2, R3, R4 and R5 = H, R6 = 5-benzyloxy and X1 = OH), m.p. 93°-95° C., is prepared by lithium aluminum hydride reduction of ethyl 5-benzyloxy-3-indoleglyoxalate (British Pat. No. 778,823) according to the procedure of Example 309. Subsequent treatment of 5-benzyloxy-3-tryptophol with the ketone, acetone, according to the procedure of Example 785 affords 6-benzyloxy-1,1-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole (VII; R1M CH3), nmr (CDCl3) δ1.53 (6H), 2.73 (t, 2H), 4.03 (t, 2H), 5.10 (2H), 6.67-7.83 (9H). The latter compound is then N-alkylated with the organic halide, dimethylaminoethyl chloride, according to the procedure of Example 838 to afford 6-benzyloxy-1,1-dimethyl-9-[2-(dimethylamino)ethyl]-1,3,4,9-tetrahydropyrano[3,4-b]indole, which on treatment with hydrochloric acid gives the corresponding hydrochloric acid addition salt thereof, m.p. 209° C.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][C@@H:10]([CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:11]([O:13][CH3:14])=[O:12].Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]Br>C(O)(C)(C)C>[C:20]([O:19][C:17]([NH:16][CH2:15][C@H:10]([N:9]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[C:11]([O:13][CH3:14])=[O:12])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: BrCCCCCBr
Reactant: COC(=O)[C@@H](N)CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CNC(=O)OC(C)(C)C)N1CCCCC1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
14.4 ml (104 mmol) of triethylamine are added to a solution of 8.0 g (31 mmol) of commercial methyl (S)-2-amino-3-tert-butoxycarbonylaminopropanoate hydrochloride in 160 ml of tert-butanol, and then the reaction medium is stirred for 30 min at 40° C., and filtered in order to remove the triethylammonium salts. 6 ml (44 mmol) of 1,5-dibromopentane are added to the filtrate thus obtained, and the reaction medium is heated at 80° C. for 3 days. After the insoluble material has been filtered off, the filtrate is concentrated under vacuum. The crude residue is purified by chromatography on silica gel, elution being carried out with a 70/30 heptane/ethyl acetate mixture. 5.3 g (59%) of methyl(S)-3-tert-butoxycarbonylamino-2-piperidin-1-ylpropanoate are obtained in the form of a colorless oil.
Reaction SMILES: [OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([O:12][C:13](=[O:17])[C:14]([CH3:16])=[CH2:15])([CH2:5]3)[CH2:3]1)[CH2:9]2.[CH2:18]([O:20][CH:21]=[CH2:22])[CH3:19].C([O-])([O-])=O.[Na+].[Na+]>O1CCCC1.Cl>[CH2:18]([O:20][CH:21]([O:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([O:12][C:13](=[O:17])[C:14]([CH3:16])=[CH2:15])([CH2:5]3)[CH2:3]1)[CH2:9]2)[CH3:22])[CH3:19]
Reactant: C=C(C)C(=O)OC12CC3CC(CC(O)(C3)C1)C2
Reactant: C=COCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C(C)C(=O)OC12CC3CC(C1)CC(OC(C)OCC)(C3)C2
Temperature: 25 °C
Reaction time: 72 h
Yield: 97.3 %

Procedure:
Under a nitrogen atmosphere, 23.6 g (0.1 mols) of 1-hydroxy-3-methacryloyloxyadamantane (HAMA) was dissolved in 100 ml of tetrahydrofuran (THF) and 21.6 g (0.3 mols) of vinyl ethyl ether and 0.1 ml (1 mmol) of hydrochloric acid were added, followed by stirring at room temperature for 3 days. The reaction solution was neutralized with an aqueous Na2CO3 solution added and, after phase separation, the upper layer was washed with water so as to adjust the pH to 7. MgSO4 was added and the solution was dehydrated and filtered, and then concentrated to dryness to obtain 30 g of 1-(1′-ethoxyethoxy)-3-methacryloyloxyadamantane (EEAM) (yield: 99%)
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH2:4]Cl.[CH2:11]([O:13][C:14]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=[O:15])[CH3:12].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH2:4][N:19]1[CH2:18][CH2:17][N:16]([C:14]([O:13][CH2:11][CH3:12])=[O:15])[CH2:21][CH2:20]1
Reactant: CCOC(=O)N1CCNCC1
Reactant: ClCc1cc(Cl)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(Cc2cc(Cl)ccc2Cl)CC1
Temperature: 25 °C
Yield: 61.3 %

Procedure:
2,5-Dichlorobenzyl chloride (2.01 g) was added to a mixture of 1.94 g of 1-ethoxycarbonylpiperazine and 3.45 g of anhydrous potassium carbonate in 20 ml of N,N-dimethylformamide stirred at room temperature in nitrogen atmosphere. After 24 h of stirring at the same temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The organic phase, which was dried on anhydrous Na2SO4, was evaporated to dryness under vacuum. The oily residue was purified via flash chromatography (petrolium ether-ethyl acetate 85:15) giving 2 g (63%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([S:14]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])(=[O:16])=[O:15])=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].C(O)C.[OH-].[Na+].Cl>O>[Cl:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([S:14]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])(=[O:16])=[O:15])=[CH:9][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)c1cc(S(=O)(=O)Nc2ccccc2F)c(F)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc(S(=O)(=O)Nc2ccccc2F)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To ethyl 2-chloro-4-fluoro-5-{[(2-fluorophenyl)amino]sulfonyl}benzoate (1.45 g) was added ethanol (6.4 mL) followed by a solution of NaOH (0.398 g, 9.96 mmol) in water (6.4 mL). The reaction was stirred at ambient temperature for 1 hour. To the mixture was added 1 N HCl (22.8 mL), and the mixture was stirred for 30 minutes. The solids were collected by filtration, washed with water (2×4 mL), and dried in a vacuum oven at 45° C. for 2.5 days to give 2-chloro-4-fluoro-5-{[(2-fluorophenyl)amino]sulfonyl}benzoic acid: 1H NMR (400 MHz, DMSO-d6) δ ppm 13.89 (s, 1H), 10.67 (s, 1H), 8.09 (d, J=7.7, 1H), 7.88 (d, J=9.9, 1H), 7.32-7.11 (m, 4H); MS (ESI) m/z 346 (M−H)−.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]1[C:10]([N+:11]([O-])=O)=[CH:9][N:8]=[C:7]([N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[CH:6]=1.[H][H]>C(O)C.[Pt]=O>[N:14]1([C:7]2[CH:6]=[C:5]3[CH:4]=[CH:3][NH:11][C:10]3=[CH:9][N:8]=2)[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: [H][H]
Reactant: CN(C)C=Cc1cc(-n2cncn2)ncc1[N+](=O)[O-]
Agent: O=[Pt]
Solvent: CCO
Product: c1ncn(-c2cc3cc[nH]c3cn2)n1
Yield: 50.3 %

Procedure:
N,N-Dimethyl-2-(5-nitro-2-(1,2,4-triazol-1-yl)pyridin-4-yl)ethenamine (8 g, 31 mmol) was hydrogenated over platinum oxide (1.6 g) in ethanol (150 mL) at 30 psi of hydrogen for 1 hour. The catalyst was removed by filtration and the solvent evaporated in vacuo. The residue was chromatographed on silica eluting with ethyl acetate to afford an orange/brown solid. This was triturated with ether and the precipitate collected by filtration to give the title compound (2.89 g, 51%) as a pink solid. mp 203°-205° C. 1H NMR (360 MHz, d6 -DMSO)δ6.67 (1H, d, J=3.0 Hz), 7.76 (1H, d, J=2.9 Hz), 8.01 (1H, s), 8.23 (1H, s), 8.70 (1H, s), 9.25 (1H, s) and 11.86 (1H, br s).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].O1CCCC1>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:6][CH:5]=1
Reactant: CS(=O)(=O)Nc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 95 %

Procedure:
5% Palladium on carbon (“wet”, 11.1 g) was added to a solution of N-(4-nitro-phenyl)-methanesulfonamide (Example 3a′, 111.4 g, 0.52 mol) in tetrahydrofuran (900 mL) at 25° C. The atmosphere above the resulting suspension was replaced with hydrogen gas and the reaction mixture was maintained under 1 atmosphere of hydrogen at 25° C. for 4 days using several balloons. The mixture was then filtered through Celite and the Celite was washed with tetrahydrofuran (3×100 mL). The combined filtrate and washings were concentrated in vacuo to approximately 300 mL volume and heptane (500 mL) was added dropwise via addition funnel over 45 min at 25° C. with vigorous stirring. The resulting suspension was stirred for an additional 45 min at 25° C., and then was filtered through medium paper using a Büchner funnel. The collected solid was washed with heptane (1×150 mL) and was air-dried to afford the desired product, N-(4-amino-phenyl)-methanesulfonamide (90.7 g, 0.49 mol, 95% yield) as a beige powder. 1H NMR (400 MHz, DMSO-d6) δ 2.79 (3H, s), 5.00 (2H, s), 6.49 (2H, d, J=8.5 Hz), 6.87 (2H, d, J=8.6 Hz), 8.87 (1H, s).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8][C:9]([Cl:14])([Cl:13])[CH:10]1[O:12][CH2:11]1>C(Cl)(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:11][CH:10]([OH:12])[C:9]([Cl:14])([Cl:13])[Cl:8])[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: ClC(Cl)(Cl)C1CO1
Solvent: ClC(Cl)Cl
Product: CN1CCN(CC(O)C(Cl)(Cl)Cl)CC1
Reaction time: 144 h

Procedure:
N-methyl piperazine (2 g) is dissolved in 80 ml chloroform, and mixed with a solution of 3.22 g 3,3,3-trichloropropylene oxide in 20 ml chloroform. The mixture is allowed to stand at room temperature for 6 days. The chloroform is removed by evaporation, and ether is added to the residue, which is then collected by filtration, washed with ether and dried at room temperature under water pump vacuum, to give the heading compound, m.p. 165°-167° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:17]=[CH:16][C:11]3[B:12]([OH:15])[O:13][CH2:14][C:10]=3[CH:9]=2)=[CH:5][CH:4]=1.[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.CCN(CC)CC>C(Cl)Cl>[OH:15][B:12]1[C:11]2[CH:16]=[CH:17][C:8]([O:7][C:6]3[CH:18]=[CH:19][C:3]([CH2:2][NH:1][S:27]([C:24]4[CH:25]=[CH:26][C:21]([CH3:20])=[CH:22][CH:23]=4)(=[O:29])=[O:28])=[CH:4][CH:5]=3)=[CH:9][C:10]=2[CH2:14][O:13]1
Reactant: NCc1ccc(Oc2ccc3c(c2)COB3O)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)NCc2ccc(Oc3ccc4c(c3)COB4O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 20 mL scintillation vial containing 5-(4-aminomethyl-phenoxy)-3H-benzo[c][1,2]oxaborol-1-ol (144 mg, 0.56 mmol, 1.1 eq.), 4-methyl-benzenesulfonyl chloride (118.4 mg, 0.62 mmol, 1.1 eq.) in DCM (10.0 mL) was added Et3N (160 μL, 1.12 mmol, 2.0 eq.) drop wise. The mixture was stirred at room temperature overnight. The mixture was carefully treated with aqu. NH4Cl (10 mL) and the layers were separated. The aqueous was extracted with DCM (2×5 mL), combined organic phase was washed with H2O (10 mL), brine (10 mL), dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. The residue was applied to silica chromatography eluting with EtOAc/Heptanes (0:100 to 80:20) to give N-[4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzyl]-4-methyl-benzenesulfonamide as a white solid. LCMS (m/z) 432 (M+23); 1H NMR (400 MHz, DMSO-d6) δ ppm 1H NMR (DMSO-d6) δ: 9.11 (s, 1H), 8.08 (t, J=6.3 Hz, 1H), 7.65-7.74 (m, 3H), 7.38 (d, J=8.0 Hz, 2H), 7.23-7.31 (m, J=8.6 Hz, 2H), 6.95-7.00 (m, 2H), 6.89-6.95 (m, 2H), 4.92 (s, 2H), 3.95 (d, J=6.3 Hz, 2H), 2.38 (s, 3H).
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:6][CH2:5][C:4]([C:1]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=4)=[O:2])([CH2:11][CH2:10]2)[CH2:9][CH2:8]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: Cc1ccc(N)cc1
Product: Cc1ccc(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)cc1
Yield: 22.3 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and p-toluidine (36.0 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(4-methylphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (14.2 mg).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH2:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][CH:31]([N:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)[CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([N:28]5[CH2:33][CH2:32][CH:31]([N:34]6[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]6)[CH2:30][CH2:29]5)[CH:23]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(N)nc23)cc1
Reactant: CN1CCN(C2CCN(c3cccc(Br)c3)CC2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(C2CCN(c3cccc(Nc4nc5c(-c6ccc(S(C)(=O)=O)cc6)cccn5n4)c3)CC2)CC1

Procedure:
[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-{3-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenyl}-amine was prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (55.0 mg, 0.191 mmol) and 1-[1-(3-bromo-phenyl)-piperidin-4-yl]-4-methyl-piperazine (69.0 mg, 0.204 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (23.0 mg, 0.0421 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as a yellow solid (0.035 g, 34%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:15]([CH3:31])[C:16](=[O:30])[CH2:17][N:18]([CH2:27][C:28]#[N:29])[C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[Li+].[OH-].FC(F)(F)C(O)=[O:37]>O1CCCC1.O>[NH2:29][C:28](=[O:37])[CH2:27][N:18]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)[CH2:17][C:16]([N:15]([C@H:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH2:9][N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)[CH3:31])=[O:30]
Reactant: O=C(O)C(F)(F)F
Reactant: CN(C(=O)CN(CC#N)c1ccc(Cl)c(Cl)c1)[C@@H](CN1CCCC1)c1ccc(Br)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C(=O)CN(CC(N)=O)c1ccc(Cl)c(Cl)c1)[C@@H](CN1CCCC1)c1ccc(Br)cc1
Temperature: 77 °C
Reaction time: 0.08 h

Procedure:
N1-[(1R)-1-(4-bromophenyl)-2-(1-pyrrolidinyl)ethyl]-N2-(cyanomethyl)-N2-(3,4-dichlorophenyl)-N1-methylglycinamide (6.1 g, crude) was dissolved in 25 mL of tetrahydrofuran and treated with a solution of LiOH (3.14 g, 74.9 mmol) suspended in 10.8 mL of water. The reaction was stirred vigorously and allowed to reflux at 77° C. for 24 hours before it was determined to be complete by LCMS (Eclipse XDB C18 (4.6×250 mm); trifluoroacetic acid: 1-99% B for 10 min, ES) Rt=7.8 min and m/e 543 [M+1]+. The solvent was removed by rotary evaporation and the crude residue was purified by silica gel chromatography (330 g Redisep column, silica, 40 um, 60 Å, 90 mL/min, A: methylene chloride, B: methanol, B: 0% for 5 min, 10% for 60 min; detection at 214 nm) to give 2-[(2-amino-2-oxoethyl)(3,4-dichlorophenyl)amino]-N-[(1R)-1-(4-bromophenyl)-2-(1-pyrrolidinyl)ethyl]-N-methylacetamide (2.82 g, 5.2 mmol). MS (ES) m/e 543 [M+H]+.
Reaction SMILES: [Mg].[CH3:2][O:3][CH2:4]Cl.[CH2:6]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1>O1CCCC1>[CH3:2][O:3][CH2:4][C:14]1([OH:15])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=2[CH2:6][CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]1=2
Reactant: COCCl
Reactant: O=C1c2ccccc2CCc2ccccc21
Agent: [Mg]
Solvent: C1CCOC1
Product: COCC1(O)c2ccccc2CCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of chloromethyl methyl ether (40.2 g, 0.5 mole, freshly distilled) in dry tetrahydrofuran (80 ml) is prepared, and about 5 ml of that solution are added to a stirred mixture of magnesium turnings (12.0 g, 0.5 g - atom) and mercuric chloride (500 mg) in tetrahydrofuran (20 ml) until an exothermic reaction ensues. The flask is cooled to 0° ± 10° and the remainder of the chloromethyl methyl ether solution is added dropwise with thorough agitation. After completion of addition a solution of 10,11-dihydro-5H- dibenzo[a,b]cyclohepten-5-one (56.1 g 0.25 mole) in tetrahydrofuran is added dropwise. The reaction mixture is stirred overnight at room temperature and the complex is hydrolyzed with ice-cold ammonium chloride solution. The aqueous layer is extracted with ether (3 × 100 ml) and the combined extracts are washed with sodium chloride solution, dried and evaporated under reduced pressure to give 10,11-dihydro-5-methoxymethyl-5H-dibenzo[a,d]cyclohepten- 5-ol as an oil with b.p. 143° -144° C/0.05 mm, γmaxfilm : 3500 cm-1, 2820 cm-1.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:4]=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20].N1C=CC=CC=1>C(Cl)Cl>[CH3:18][S:19]([NH:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:4]=1)(=[O:21])=[O:20]
Reactant: CCOC(=O)Cn1cc(N)c2ccccc21
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)Cn1cc(NS(C)(=O)=O)c2ccccc21
Temperature: 0 °C
Reaction time: 4 h
Yield: 86.3 %

Procedure:
To a suspension of ethyl 2-(3-amino-1H-indol-1-yl)acetate hydrochloride (220 mg, 0.864 mmol) in dry DCM (4 ml), cooled at 0° C. under nitrogen, methanesulfonyl chloride (67.3 μl, 0.864 mmol) and dry pyridine (559 μl, 6.91 mmol) were added. After stirring at 0° C. for 4 hours, the mixture was partitioned between 5% aqueous citric acid and DCM; the organic phase was washed with water, dried over Na2SO4 and evaporated to give ethyl 2-(3-(methylsulfonamido)-1H-indol-1-yl)acetate (221 mg, 0.746 mmol, 86% yield). MS/ESI+ 319.0 [MNa]+. This product was used in the next step without any additional purification.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[OH:13][CH2:14][CH2:15][C:16]1[N:17]=[C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:19][C:20]=1[CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:48]1[CH:49]=[C:50]([C:54](=[O:56])[CH3:55])[CH:51]=[CH:52][CH:53]=1.Cl>C1COCC1.O>[CH3:21][C:20]1[O:19][C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:17][C:16]=1[CH2:15][CH2:14][O:13][C:53]1[CH:52]=[CH:51][C:50]([C:54](=[O:56])[CH3:55])=[CH:49][CH:48]=1
Reactant: CC(=O)c1cccc(O)c1
Reactant: Cc1oc(-c2ccccc2)nc1CCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1
Reaction time: 48 h
Yield: 77.2 %

Procedure:
Diethylazodicarboxylate (20.7 mL, 131.6 mmol) in THF (35 mL) was added dropwise in to a cold (0° C.) solution of 4-(2'-hydroxy-ethyl)-5-methyl-2-phenyloxazole (25.0 g, 123.0 mmol), triphenylphosphine (34.5 g, 131.6 mmol), and 3'-hydroxyacetophenone (18.0 g, 131.6 mmol) and THF (180 mL). The mixture was allowed to come to room temperature and stirred for 48 hours. Then, it was poured into H2O, acidified with HCl (2N) and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography on silica gel (hexane/EtOAc 5/1) gave a white solid (30.5 g, 77% yield, m.p. 70°-71° C.).