Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])=O.[NH4+].C([N:12]1[CH2:17][CH2:16][N:15]([C:18]([CH:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][N:29]=[CH:28][N:27]=3)[CH2:22][CH2:21]2)=[O:19])[CH2:14][CH2:13]1)C1C=CC=CC=1>[Pd].CO>[N:29]1[CH:30]=[CH:31][C:26]([N:23]2[CH2:22][CH2:21][CH:20]([C:18]([N:15]3[CH2:14][CH2:13][NH:12][CH2:17][CH2:16]3)=[O:19])[CH2:25][CH2:24]2)=[N:27][CH:28]=1
Reactant: O=C(C1CCN(c2ccncn2)CC1)N1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: O=C(C1CCN(c2ccncn2)CC1)N1CCNCC1
Yield: 94.3 %

Procedure:
Ammonium formate (1.88 g) was added to a mixture of 1-benzyl-4-[(1-[4-pyrimidinyl]-4-piperidyl)carbonyl]piperazine (2.73 g) and 10% palladium on carbon catalyst (0.55 g) in methanol (70 ml) under an atmosphere of argon. The mixture was stirred at reflux temperature for 1 hour. The cooled mixture was filtered through diatomaceous earth and the filtercake was well washed with methanol. The filtrate and washings were combined and evaporated. The residual oil was suspended in saturated aqueous sodium carbonate solution (30 ml) and the mixture was extracted with dichloromethane (4×100 ml). The dichloromethane extracts were combined, dried (Na2SO4) and evaporated to give 1-[(1-[4-pyrimidinyl]-4-piperidyl)carbonyl]piperazine (1.94 g, 94%) as an off-white solid;
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:25]([CH3:27])[CH3:26])[CH:19]=1.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([Cl:44])[C:30]=1[OH:45]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:25]([CH3:27])[CH3:26])[CH:19]=2)=[CH:3][C:2]([C:33]2[CH:34]=[C:29]([Cl:28])[C:30]([OH:45])=[C:31]([Cl:44])[CH:32]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:15][CH2:16]1
Reactant: CN(C)Cc1cccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)c1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CN(C)Cc1cccc(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)cc23)c1
Yield: 74.7 %

Procedure:
Following general procedure D, (6-bromo-4-(3-((dimethylamino)methyl)phenylamino)quinoline-3-yl)(cyclopropyl)methanone (100 mg, 0.23 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (98 mg, 0.34 mmol) to afford the desired product (87 mg, 75%) as a yellow-green solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.45 (s, 1H), 8.25 (dd, J=8.8, 1.9 Hz, 1H), 8.05 (d, J=8.8 Hz, 1H), 7.97 (s, 1H), 7.74 (m, 1H), 7.63 (m, 3H), 7.28 (s, 2H), 4.39 (s, 2H), 2.84 (m, 7H), 1.19 (m, 4H); ESI MS m/z 506 [C28H25Cl2N3O2+H]+; HPLC 98.0% (AUC), tR=11.15 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[O:13][C:12](=[O:14])[N:11]([CH2:15][C:16]3[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=3I)[C@H:10]2[CH3:27])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][C:39]([C:42]([O:44][CH3:45])=[O:43])=[CH:38][C:37]=2[CH3:46])=[CH:32][C:31]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[O:13][C:12](=[O:14])[N:11]([CH2:15][C:16]3[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=3[C:31]3[CH:32]=[C:33]([C:36]4[CH:41]=[CH:40][C:39]([C:42]([O:44][CH3:45])=[O:43])=[CH:38][C:37]=4[CH3:46])[CH:34]=[CH:35][C:30]=3[O:29][CH3:28])[C@H:10]2[CH3:27])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(B3OC(C)(C)C(C)(C)O3)c2)c(C)c1
Reactant: C[C@H]1[C@@H](c2cc(Cl)cc(Cl)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1I
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3CN3C(=O)O[C@H](c4cc(Cl)cc(Cl)c4)[C@@H]3C)c2)c(C)c1
Reaction time: 0.25 h

Procedure:
((4S,5R)-5-(3,5-dichlorophenyl)-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (100 mg, 0.1886 mmol), methyl 4′-methoxy-2-methyl-3′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)biphenyl-4-carboxylate (108 mg, 0.283 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride dichloromethane adduct (46 mg, 0.056 mmol), aqueous sodium carbonate (190 μL, 2M, 0.380 mmol) and 1,4-dioxane (2 mL) were placed in a sealed tube and subjected to microwave irradiation at 130° C. for 30 minutes and then at 135° C. for 15 minutes to complete the reaction. The crude reaction mixture was purified by preparative TLC on SiO2 (eluted sequentially with 30% ethyl acetate in hexanes, 70% dichloromethane in hexanes and then 80% dichloromethane in hexanes) to afford methyl 2″-{[(4S,5R)-5-(3,5-dichlorophenyl)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]methyl}-4′-methoxy-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate as a white solid. LCMS calc.=657.13; found=658.46 (M+1)+. 1H NMR signals are doubled because of atropisomerism 1H NMR (CDCl3, 500 MHz) δ 7.94 (d, J=7 Hz, 1H), 7.87 (d, J=8.5 Hz, 1H), 7.70 (s, 0.5H), 7.65-7.61 (m, 1.5H), 7.47-7.36 (m, 3H), 7.32 (d, J=2 Hz, 0.5H), 7.29-7.23 (m, 1.5H), 7.11 (dd, J=6.3, 2.0 Hz, 1H), 7.08-7.02 (m, 1.5H), 7.00 (dd, J=8.3, 2.0 Hz, 0.5H), 5.41 (d, J=8.5 Hz, 0.5H), 5.16 (d, J=8.0 Hz, 0.5H), 4.91 (d, J=16 Hz, 0.5H), 4.85 (d, J=16.5 Hz, 0.5H), 4.17 (d, J=16 Hz, 0.5H), 3.98-3.90 (m, 3.5H), 3.856, 3.851 (s, 3H), 3.74-3.66 (m, 1H), 2.36, 2.32 (s, 3H), 0.55 (d, J=7 Hz, 1.5H), 0.43 (d, J=6 Hz, 1.5H).
Reaction SMILES: [C:1]([O:5][CH:6]([C:12]1[C:16](B2OC(C)(C)C(C)(C)O2)=[C:15]([CH3:26])[S:14][C:13]=1[CH3:27])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)S(OC1CCC2(OCCO2)CC=1)(=O)=O.C(OC(C1[C:61]([C:62]2[CH2:71][CH2:70][C:65]3(OCCO3)[CH2:64][CH:63]=2)=C(C)SC=1C)C(OCC)=O)(C)(C)C>>[C:1]([O:5][CH:6]([C:12]1[C:16]([C:61]2[CH2:62][CH2:71][CH2:70][CH2:65][CH2:64][CH:63]=2)=[C:15]([CH3:26])[S:14][C:13]=1[CH3:27])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)sc(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)sc(C)c1C1=CCC2(CC1)OCCO2
Agent: O=S(=O)(OC1=CCC2(CC1)OCCO2)C(F)(F)F
Product: CCOC(=O)C(OC(C)(C)C)c1c(C)sc(C)c1C1=CCCCCC1

Procedure:
Using the procedure described in example 29, step 2, ethyl 2-(tert-butoxy)-2-[2,5-dimethyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-3-yl]acetate (28f) (100 mg, 0,246 mmol) is converted, by reaction with 1,4-dioxaspiro[4.5]dec-7-en-8-yl trifluoromethanesulfonate (34a) and after purification by flash chromatography on silica gel (cyclohexane/ethyl acetate 90/10), to ethyl 2-(tert-butoxy)-2-(4-{1,4-dioxaspiro[4.5]dec-7-en-8-yl}-2,5-dimethylthiophen-3-yl)acetate (34b) (39 mg, 0.10 mmol, 39%).
Reaction SMILES: O[Li].O.[C:4]([O:8][C:9]([N:11]([CH3:46])[C@@H:12]([CH3:45])[C:13]([NH:15][C@H:16]1[CH2:22][O:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]([CH2:27][C:28]2[C:37]([O:38][CH3:39])=[CH:36][CH:35]=[C:34]3[C:29]=2[CH:30]=[CH:31][C:32]([C:40]([O:42]C)=[O:41])=[CH:33]3)[C:17]1=[O:44])=[O:14])=[O:10])([CH3:7])([CH3:6])[CH3:5].OS([O-])(=O)=O.[K+]>O.CO>[C:4]([O:8][C:9]([N:11]([CH3:46])[C@@H:12]([CH3:45])[C:13]([NH:15][C@H:16]1[CH2:22][O:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]([CH2:27][C:28]2[C:37]([O:38][CH3:39])=[CH:36][CH:35]=[C:34]3[C:29]=2[CH:30]=[CH:31][C:32]([C:40]([OH:42])=[O:41])=[CH:33]3)[C:17]1=[O:44])=[O:14])=[O:10])([CH3:6])([CH3:7])[CH3:5]
Reactant: COC(=O)c1ccc2c(CN3C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)COc4ccccc43)c(OC)ccc2c1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li]O
Solvent: CO
Solvent: O
Product: COc1ccc2cc(C(=O)O)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)COc2ccccc21
Temperature: 50 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
LiOH.H2O (24.0 mg, 573 μmol, Eq: 3) was dissolved in water and the solution was added to a solution of methyl 5-(((S)-3-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-4-oxo-3,4-dihydrobenzo[b][1,4]oxazepin-5(2H)-yl)methyl)-6-methoxy-2-naphthoate (113 mg, 191 μmol, Eq: 1.00) in MeOH (3 mL) and the mixture was heated to 50° C. for 1 h and then to 60° C. for 1 h. The mixture was cooled, KHSO4 solution was added and the mixture extracted with EtOAc. The combined extracts were concentrated and the residue purified by silica gel chromatography to afford 5-(((S)-3-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-4-oxo-3,4-dihydrobenzo[b][1,4]oxazepin-5(2H)-yl)methyl)-6-methoxy-2-naphthoic acid (103 mg, 93%) as a white powder.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1.[I:11][C:12]1[CH:13]=[N:14][NH:15][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[I:11][C:12]1[CH:13]=[N:14][N:15]([CH2:2][CH2:3][O:4][CH:5]2[CH2:10][CH2:9][CH2:8][CH2:7][O:6]2)[CH:16]=1
Reactant: Ic1cn[nH]c1
Reactant: BrCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Ic1cnn(CCOC2CCCCO2)c1
Temperature: 25 °C
Yield: 28.7 %

Procedure:
At r.t. to a solution of 2-(2-bromoethoxy)tetrahydro-2H-pyran (210 μL, 1.4 mmol) (Aldrich Cat. No. 475394) in acetonitrile (6 mL) was added 4-iodo-1H-pyrazole (0.25 g, 1.3 mmol) (Aldrich Cat. No. 213993), followed by cesium carbonate (0.63 g, 1.9 mmol). The mixture was stirred at r.t. over a weekend. The solid was filtered off, then washed with acetonitrile. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (0.12 g). LCMS (M-84)+=239.0.
Reaction SMILES: [C:1]([N:4]([CH2:26][C@@H:27]1[O:31][C:30](=[O:32])[N:29]([C:33]2[CH:38]=[CH:37][C:36]([N:39]3[CH2:46][C:45]4[C:41](=[N:42][N:43]([CH3:47])[CH:44]=4)[CH2:40]3)=[C:35]([F:48])[CH:34]=2)[CH2:28]1)[C:5]([O:7][CH2:8][O:9][C:10](=[O:25])[CH2:11][O:12][P:13]([O:20]C(C)(C)C)([O:15]C(C)(C)C)=[O:14])=[O:6])(=[O:3])[CH3:2].Cl.C(OCC)C>ClCCl>[C:1]([N:4]([CH2:26][C@@H:27]1[O:31][C:30](=[O:32])[N:29]([C:33]2[CH:38]=[CH:37][C:36]([N:39]3[CH2:46][C:45]4[C:41](=[N:42][N:43]([CH3:47])[CH:44]=4)[CH2:40]3)=[C:35]([F:48])[CH:34]=2)[CH2:28]1)[C:5]([O:7][CH2:8][O:9][C:10](=[O:25])[CH2:11][O:12][P:13]([OH:20])([OH:15])=[O:14])=[O:6])(=[O:3])[CH3:2]
Reactant: CC(=O)N(C[C@H]1CN(c2ccc(N3Cc4cn(C)nc4C3)c(F)c2)C(=O)O1)C(=O)OCOC(=O)COP(=O)(OC(C)(C)C)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)N(C[C@H]1CN(c2ccc(N3Cc4cn(C)nc4C3)c(F)c2)C(=O)O1)C(=O)OCOC(=O)COP(=O)(O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.5 %

Procedure:
To a solution of 23 (20 mg, 0.03 mmol) in dichloromethane (1 mL) under nitrogen was added dropwise a solution of 1N HCl in diethyl ether (2.0 mL, 2.0 mmol). The reaction mixture was stirred for 1 h at rt, concentrated in vacuo, and purified directly by HPLC (C-18 column, 10-70% gradient elution, MeCN:H2O with 0.1% TFA) to give 5 mg (25%) of the title compound. 1H NMR (400 MHz, DMSO-d6): δ 7.53 (s, 1H), 7.42 (dd, 1H), 7.15 (dd, 1H), 6.87 (dd, 1H), 5.88 (s, 2H), 4.79-4.72 (m, 1H), 4.53 (d, 2H), 4.48-4.46 (m, 4H), 4.15-4.07 (m, 2H), 3.88 (dd, 1H), 3.85 (s, 3H), 3.76 (dd, 1H), and 2.46 (s, 3H). MS 586 (M+1)+
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[C:8]([F:24])=[CH:9][C:10]([O:22][CH3:23])=[CH:11][C:12]=3[C@:13]32[N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]3)=[CH:4][CH:3]=1.Cl.[F:26][C:27]1([F:33])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:26][C:27]1([F:33])[CH2:32][CH2:31][N:30]([C:2]2[CH:15]=[C:14]3[C:5]([O:6][C:7]4[C:8]([F:24])=[CH:9][C:10]([O:22][CH3:23])=[CH:11][C:12]=4[C@:13]43[N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]4)=[CH:4][CH:3]=2)[CH2:29][CH2:28]1
Reactant: COc1cc(F)c2c(c1)[C@]1(COCC(N)=N1)c1cc(Br)ccc1O2
Reactant: FC1(F)CCNCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(F)c2c(c1)[C@]1(COCC(N)=N1)c1cc(N3CCC(F)(F)CC3)ccc1O2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A vial was charged with (S)-7′-bromo-4′-fluoro-2′-methoxy-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-5-amine (200 mg, 0.509 mmol), chloro(2-dicyclohexylphosphino-2′,6′-di-1-propoxy-1,1′-biphenyl)[2-(2-aminoethyl)phenyl] palladium(II) methyl-t-butylether adduct (18.53 mg, 0.025 mmol), 4,4-difluoropiperidine hydrochloride (160 mg, 1.017 mmol) and 1 ml of THF. The mixture was cooled to 0° C. and LHMDS (1M in THF) (2035 μL, 2.035 mmol) was added, and the vial was sealed and stirred at RT for 2 hr. At this point more chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)[2-(2-aminoethyl)phenyl] palladium(II) methyl-t-butylether adduct (18.53 mg, 0.025 mmol), (18.53 mg, 0.025 mmol) was added followed by LHMDS solution (1 ml) and stirring continued for another hour. The mixture was quenched by addition of 2 ml of water and extracted with EtOAc. The combined organic fractions were concentrated and purified by chromatography [5-50% DCM/MeOH/NH4OH (90:10:1)] to afford (S)-7′-(4,4-difluoropiperidin-1-yl)-4′-fluoro-2′-methoxy-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-5-amine as yellowish foam.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:22])[CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:11][CH:10]=1)C1C=CC=CC=1.OC1C=CC(NC(C2C=CC=CN=2)=O)=CC=1>>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:22])[CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:13][CH:14]=1
Reactant: CS(=O)(=O)CC(=O)Nc1ccc(OCc2ccccc2)cc1
Agent: O=C(Nc1ccc(O)cc1)c1ccccn1
Product: CS(=O)(=O)CC(=O)Nc1ccc(O)cc1

Procedure:
This compound was prepared from N-(4-benzyloxy-phenyl)-2-methanesulfonyl-acetamide, using the same method used to prepare of pyridine-2-carboxylic acid (4-hydroxyphenyl)amide. The product was purified by flash chromatography, on silica gel, eluted with 5 to 10% methanol in DCM, to give the product, 3.45 g (92%) as a colorless solid. MS m/z 230 (MH+). 1H NMR(DMSO-d6) δ 3.18 (s, 3H), 4.22 (s, 2H), 6.72 (d, 2H), 7.36 (d, 2H), 9.35(br s, 1H) and 10.17 (s, 1H). Anal. calcd for C9H11N4OS: C, 47.15; H, 4.84; N, 6.11. Found: C, 47.04; H, 4.79; N, 6.04.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:19][CH2:18][N:17](C(OCC2C=CC=CC=2)=O)[CH2:16][CH2:15][N:14]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[Si](C)(C)C>>[CH2:1]([O:8][C:9]([N:11]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15][N:14]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CCN(C(=O)OCc2ccccc2)CCN(C(=O)OCc2ccccc2)CC1
Agent: C[Si](C)(C)I
Product: O=C(OCc1ccccc1)N1CCNCCN(C(=O)OCc2ccccc2)CC1

Procedure:
From N,N′,N″-tris(benzyloxycarbonyl)-1,4,7-triazacyclononane (1.3.13.8) and iodotrimethylsilane.
Reaction SMILES: [C:1]([C@@H:4]([NH:13][C@H:14]([C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24]([OH:26])=[O:25])=[O:21])[CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([OH:3])=[O:2].[C:30]([NH2:34])(=[O:33])[CH:31]=O.C(N)(=O)CO.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O>[Pd]>[C:1]([C@@H:4]([NH:13][C@H:14]([C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24]([OH:26])=[O:25])=[O:21])[CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:31][C:30](=[O:33])[NH2:34])[CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)([OH:3])=[O:2]
Reactant: NC(=O)C=O
Reactant: NCCCC[C@H](N[C@@H](CCc1ccccc1)C(=O)O)C(=O)N1CCC[C@H]1C(=O)O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [Pd]
Agent: NC(=O)CO
Product: NC(=O)CNCCCC[C@H](N[C@@H](CCc1ccccc1)C(=O)O)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
In the manner described above in Example 1, N-[N2 (1(S)-carboxy-3-phenylpropyl)-L-lysyl]-L-proline and glyoxylic acid amide (which can be prepared by the oxidation of glycolamide with pyridinum dichromate) were hydrogenated in the presence of 10% Pd on carbon catalyst to yield N-[N2 -(1(S)-carboxy-3-phenylpropyl)-N6 -carbamoylmethyl-L-lysyl]-L-proline.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:35][O:36][C:37]1[C:42](B(O)O)=[CH:41][CH:40]=[CH:39][N:38]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[N:29]=[C:30]([C:42]5[C:37]([O:36][CH3:35])=[N:38][CH:39]=[CH:40][CH:41]=5)[CH:31]=[CH:32][CH:33]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: COc1ncccc1B(O)O
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5cccnc5OC)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using 1-{4′-[4-(6-bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 2-methoxypyridine-3-boronic acid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:29])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:16]=1)[C:11]([CH3:28])([CH3:27])[CH2:10]2)=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1.O>[Cl:29][C:7]1[CH:8]=[C:9]2[C:14](=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=1)[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[CH:16]=1)[C:11]([CH3:28])([CH3:27])[CH2:10]2
Reactant: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(N3CCOCC3)c1)C(C)(C)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)Cc2cc(Cl)cc(C(=O)O)c2NC1c1cccc(N2CCOCC2)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 89.8 %

Procedure:
To a stirred mixture solution of 6-chloro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (400 mg, 1.0 mmol) in methanol (15.0 mL) and tetrahydrofuran (15.0 mL) was added 50% sodium hydroxide in water (2.0 mL). The reaction mixture was stirred at 70° C. for 6 hours. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 6-chloro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (360 mg, 90%) as a light yellow solid: LC/MS m/e calcd for C22H25ClN2O3 (M+H)+: 401.91, observed: 401.1.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].C([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[N:18][C:19]([NH:41][CH:42]3[CH2:44][CH2:43]3)=[C:20]([N:25]3[CH2:30][CH2:29][CH:28]([CH:31]([C:33]4[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=4[F:40])[F:32])[CH2:27][CH2:26]3)[N:21]=2)[CH2:16]1)C1C=CC=CC=1>C1COCC1.[OH-].[OH-].[Pd+2]>[CH:42]1([NH:41][C:19]2[N:18]=[C:17]3[CH2:16][NH:15][CH2:24][CH2:23][C:22]3=[N:21][C:20]=2[N:25]2[CH2:30][CH2:29][CH:28]([CH:31]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=3[F:40])[F:32])[CH2:27][CH2:26]2)[CH2:43][CH2:44]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: Fc1ccc(C(F)C2CCN(c3nc4c(nc3NC3CC3)CN(Cc3ccccc3)CC4)CC2)c(F)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: Fc1ccc(C(F)C2CCN(c3nc4c(nc3NC3CC3)CNCC4)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 6-benzyl-N-cyclopropyl-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (93.5 mg, 0.150 mmol) and Pd(OH)2 (20 wt %, 10 mg, 0.014 mmol) in THF (750 μL) was stirred at room temperature under an atmosphere of hydrogen gas (balloon). After 2 h, the mixture was directly purified by HPLC Method A to give the title compound as a TFA salt (67.7 mg, 85%) as a yellow oil. 1H NMR (400 MHz, methanol-d4) δ ppm 0.51-0.57 (m, 2H), 0.75-0.81 (m, 2H), 1.43 (br d, J=13.1 Hz, 1H), 1.52-1.72 (m, 2H), 1.94-2.13 (m, 2H), 2.59-2.72 (m, 3H), 2.97 (t, J=6.3 Hz, 2H), 3.40-3.50 (m, 2H), 3.51-3.56 (m, 2H), 3.98 (s, 1H), 4.22 (s, 2H), 5.51 (dd, J=46.2, 7.3 Hz, 1H), 6.96-7.08 (m, 2H), 7.46-7.54 (m, 1H); ESI-MS m/z [M+H]+ 418.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH:15]([CH3:17])[CH3:16])[N:13]=[C:12]([CH2:18][OH:19])[C:11]=2[CH2:20][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(N(CC)CC)C.[CH3:34][N:35]=[C:36]=[O:37]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH:15]([CH3:17])[CH3:16])[N:13]=[C:12]([CH2:18][O:19][C:36](=[O:37])[NH:35][CH3:34])[C:11]=2[CH2:20][C:21]2[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CN=C=O
Reactant: CC(C)n1nc(CO)c(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)OCc1nn(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)c1Cc1ccncc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution containing 45 mg of 5-(3,5-dichlorophenylthio)-1-isopropyl-4-[(4-pyridyl)methyl]-1H-pyrazole-3-methanol in 4 ml of anhydrous dichloromethane under nitrogen at room temperature was treated with 0.017 ml of triethylamine and 0,007 ml of methyl isocyanate. The mixture was stirred at room temperature for 1 h. The mixture was partitioned between ethyl acetate and water then extracted with dichloromethane three times. The combined extracts were washed with brine then dried over anhydrous magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using methanol/dichloromethane (0:1 to 1:49) for the elution to give 36 mg of methylcarbamic acid [5-(3,5-dichlorophenylthio)-1-isopropyl-4-[(4-pyridyl)methyl]-1H-pyrazol-3-yl]methyl ester as a yellow gum. Mass spectrum (ESI) m/z 465 [M+H]+. 1H NMR (DMSO) 1.30 (d, 6H), 2.55 (d, 3H), 3.90 (s, 2H), 5.05 (s, 2H), 6.77 (s, 2H), 7.05 (d, 2H), 7.12 (m, 1H), 7.37 (s, 1H), 8.30 (d, 2H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)=[O:12])=[CH:7][N:6]=1)=[O:4].CO.[OH-].[Na+:24]>>[Cl:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[CH2:13][S:11]([C:8]1[CH:9]=[CH:10][C:5]([C:3]([O-:4])=[O:2])=[N:6][CH:7]=1)=[O:12].[Na+:24]
Reactant: COC(=O)c1ccc(S(=O)Cc2cccc(Cl)c2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])c1ccc(S(=O)Cc2cccc(Cl)c2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the stirred mixture of 9 g of 5-(m-chlorobenzylsulfinyl)-2-pyridinecarboxylic acid methyl ester and 40 ml of N aqueous sodium hydroxide methanol is added until dissolution occurs. The solution is heated at the steam bath for 10 minutes and stirred overnight at room temperature. It is evaporated, the residue taken up in the minimum amount of hot water, the solution filtered, the filtrate cooled and the precipitate formed collected, to yield the sodium 5-(m-chlorobenzylsulfinyl)-2-pyridinecarboxylate.
Reaction SMILES: O.[SH:2][CH2:3][CH2:4][C:5]([NH:7][N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:6].S[CH2:17][CH2:18][C:19](NN1CCC[C@H]1C(O)=O)=O.C(N=NNC1C=CC(C)=CC=1)CC>CCOCC>[SH:2][CH2:3][CH2:4][C:5]([NH:7][N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([O:12][CH2:17][CH2:18][CH3:19])=[O:11])=[O:6]
Reactant: O=C(CCS)NN1CCC[C@H]1C(=O)O
Agent: CCCN=NNc1ccc(C)cc1
Solvent: O
Solvent: CCOCC
Product: CCCOC(=O)[C@@H]1CCCN1NC(=O)CCS

Procedure:
To a stirred suspension of 6.81 g. of 1-[(3-mercapto-1-oxopropyl)amino]-L-proline, hemihydrate in 50 ml. of ether, there is added dropwise a solution of 8.75 g. of 1-propyl-3-p-tolyltriazene in 100 ml. of ether and the mixture is heated to reflux for 4 hours. The reaction mixture is then cooled, filtered and extracted twice with 50 ml. portions of 5% hydrochloric acid and then with 50 ml. portions of 5% sodium bicarbonate solution. The ether solution is then washed with 100 ml. of saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to yield the crude product.