Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH2:9][C:10]1[NH:14][N:13]=[N:12][N:11]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:23][CH2:24][F:25]>CN(C=O)C>[C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH2:9][C:10]1[N:14]([CH2:23][CH2:24][F:25])[N:13]=[N:12][N:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCc1nnn[nH]1
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCc1nnnn1CCF
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution comprising [2-(1H-Tetrazol-5-yl)-ethyl]-carbamic acid tert-butyl ester (EP 449523) (0.125 g, 0.586 mmol) in DMF (5 ml) is added caesium carbonate (0.23 g, 0.703 mmol) followed by 1-bromo-2-fluoroethane (0.174 ml, 2.344 mmol) and the reaction mixture is left to stir at room temperature for 3 days. The solvent is removed in vacuo and the crude residue is purified by flash silica chromatography (elution 3:2 increasing to 1:4 hexane/ethyl acetate) to afford the titled compound and {2-[1-(2-Fluoro-ethyl)-1H-tetrazol-5-yl]-ethyl}-carbamic acid tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]=[C:12]=[O:13])=[O:4].[C:14]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>ClCCCl>[C:14]([N:21]1[CH2:22][CH2:23][N:24]([C:12]([NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:3]([O:2][CH3:1])=[O:4])=[O:13])[CH2:25][CH2:26]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COC(=O)c1ccccc1N=C=O
Solvent: ClCCCl
Product: COC(=O)c1ccccc1NC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1.5 h
Yield: 55.1 %

Procedure:
To a stirring solution of 2-methoxycarbonylphenyl isocyanate (5.44 g, 30.71 mmol) in 1,2-dichloroethane (30 mL) was added Boc-piperazine (5.72 g, 30.71 mmol). After 1.5 h, the solvent was removed in vacuo and the solid residue was suspended in diethyl ether with vigorous stirring, then filtered and dried to give 6.15 g (55%) of a white solid. A second crop was isolated by adding hexanes to the mother liquor. The precipitate was again filtered and dried in vacuo to give 3.32 g (30%) of a white solid.
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:6][CH2:5][C:4]2([C:11]3=[N:12][CH:13]=[CH:14][N:10]3[C:9]3[CH:15]=[CH:16][CH:17]=[CH:18][C:8]=3[O:7]2)[CH2:3][CH2:2]1.O1CCOCC1.[ClH:32]>>[ClH:32].[ClH:32].[NH:1]1[CH2:6][CH2:5][C:4]2([O:7][C:8]3[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=3[N:10]3[CH:14]=[CH:13][N:12]=[C:11]23)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1ccccc1-n1ccnc12
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc2c(c1)OC1(CCNCC1)c1nccn1-2

Procedure:
tert-Butyl spiro[imidazo[2,1-c][1,4]benzoxazine-4,4′-piperidine]-1′-carboxylate (138 mg, 0.40 mmol) was stirred for 10 min in 4M HCl in dioxane (2 mL of 4 M, 8.00 mmol). The reaction was evaporated to dryness to yield the spiro[benzo[b]imidazo[1,2-d][1,4]oxazine-4,4′-piperidine] dihydrochloride (97 mg, quantitative) that was used in next step without further purification. ESI-MS m/z calc. 241.1, found 242.3 (M+1)+. Retention time 0.40 minutes (3 min run).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:32]=[CH:31][C:16]([C:17]([O:19][CH2:20][C:21]([O:23]CC2C=CC=CC=2)=[O:22])=[O:18])=[CH:15][C:14]=1[O:33][CH2:34][CH:35]1[CH2:37][CH2:36]1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO>CCOC(C)=O.[Pd]>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:32]=[CH:31][C:16]([C:17]([O:19][CH2:20][C:21]([OH:23])=[O:22])=[O:18])=[CH:15][C:14]=1[O:33][CH2:34][CH:35]1[CH2:36][CH2:37]1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(c1ccc(C(=O)OCC(=O)OCc2ccccc2)cc1OCC1CC1)S(C)(=O)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N(c1ccc(C(=O)OCC(=O)O)cc1OCC1CC1)S(C)(=O)=O
Reaction time: 2 h
Yield: 79 %

Procedure:
2-(benzyloxy)-2-oxoethyl 4-(N-(tert-butoxycarbonyl)methylsulfonamido)-3-(cyclopropylmethoxy)benzoate (2.6 g, 4.87 mmol) was suspended in EtOAc (30 ml) and MeOH (10 ml) in a 250 ml Parr bottle; 10% Pd/C (0.176 g, 0.165 mmol) was added; and the mixture was hydrogenated at the Parr apparatus for 2 hours (H2 pressure: 30 psi), then the catalyst was filtered over a pad of celite and the solvent was evaporated to dryness; 2-(4-(N-(tert-butoxycarbonyl)methylsulfonamido)-3-(cyclopropylmethoxy)benzoyloxy)-acetic acid was obtained as a white amorphous solid (1.7 g, 3.83 mmol, 79% yield, MS/ESI+ 465.9 [MNa]+) and used as such in the following reaction without further purification.
Reaction SMILES: [F:1][C:2]1([F:13])[O:6][C:5]2[CH:7]=[C:8]([F:12])[C:9]([NH2:11])=[CH:10][C:4]=2[O:3]1.[N:14]([O-])=O.[Na+].[CH3:18][O:19][CH2:20][C:21](=[O:27])[CH2:22][C:23]([O:25][CH3:26])=[O:24].CC([O-])=O.[Na+]>Cl.O.CCO>[CH3:18][O:19][CH2:20][C:21](=[O:27])[C:22](=[N:14][NH:11][C:9]1[C:8]([F:12])=[CH:7][C:5]2[O:6][C:2]([F:1])([F:13])[O:3][C:4]=2[CH:10]=1)[C:23]([O:25][CH3:26])=[O:24]
Reactant: COCC(=O)CC(=O)OC
Reactant: Nc1cc2c(cc1F)OC(F)(F)O2
Reactant: O=N[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COCC(=O)C(=NNc1cc2c(cc1F)OC(F)(F)O2)C(=O)OC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
To a suspension of 2,2,6-trifluoro-1,3-benzodioxol-5-amine (4.95 g, 25.9 mmol) in 6 M HCl aqueous solution (25.9 mL) was added a solution of NaNO2 (2.15 g, 31.1 mmol) in water (5.2 mL) at 0° C. To a suspension of methyl 4-methoxy-3-oxobutanoate (3.35 mL, 25.9 mmol) and NaOAc (38.9 g) in EtOH (44 mL) was added the above solution at 0° C. The mixture was stirred at 0° C. for 10 min. The precipitates were collected by filtration, washed with water, dissolved in EtOAc, washed with brine and NaHCO3 aqueous solution, dried over MgSO4, filtered and concentrated in vacuo to yield the title compound (6.31 g, 70% yield) as a red solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 3.33 (3H, s), 3.82 (3H, s), 4.66 (2H, s), 7.57-7.92 (2H, m), 12.32 (1H, brs).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[N:8]=[CH:7][C:6]([C@H:9]([NH:11][C:12]2[C:13]3[CH2:21][NH:20][CH2:19][CH2:18][C:14]=3[N:15]=[CH:16][N:17]=2)[CH3:10])=[CH:5][CH:4]=1.[Cl:24][C:25]1[CH:26]=[CH:27][C:28](F)=[C:29]([CH:32]=1)[C:30]#[N:31].C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([N:20]2[CH2:19][CH2:18][C:14]3[N:15]=[CH:16][N:17]=[C:12]([NH:11][C@@H:9]([C:6]4[CH:7]=[N:8][C:3]([C:2]([F:1])([F:22])[F:23])=[CH:4][CH:5]=4)[CH3:10])[C:13]=3[CH2:21]2)=[C:29]([CH:32]=1)[C:30]#[N:31]
Reactant: C[C@@H](Nc1ncnc2c1CNCC2)c1ccc(C(F)(F)F)nc1
Reactant: N#Cc1cc(Cl)ccc1F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Nc1ncnc2c1CN(c1ccc(Cl)cc1C#N)CC2)c1ccc(C(F)(F)F)nc1
Yield: 52 %

Procedure:
A mixture of (R)—N-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (500 mg, 1.55 mmol), 5-chloro-2-fluorobenzonitrile (360 mg, 2.3 mmol), N,N-diisopropylethylamine (540 mL, 3.1 mmol), and acetonitrile (3.0 mL) was subjected to microwave irradiation at 180° C. for 2 h. Then more 5-chloro-2-fluorobenzonitrile (360 mg) was added and the mixture was subjected to microwave irradiation at 180° C. for another 2 h. After that an additional 5-chloro-2-fluorobenzonitrile (360 mg) was added and the mixture was subjected to microwave irradiation at 180° C. for an additional 2 h. After cooling the mixture was concentrated in vacuo and the residue was purified by silica gel column (0-100% EtOAc/hexane) and the obtained solid was washed with ether to yield an off-white solid (370 mg, 51%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]=[C:5]2[NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:21][CH:20]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34].C(N(CC)CC)C.[ClH:47]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[ClH:47].[C:33]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH:6]=[C:5]2[NH:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)=[CH:23][CH:24]=1)(=[O:35])[CH3:34]
Reactant: Nc1ccc2nc(-c3ccccc3)cc(Nc3ccc(OCC4CCCCC4)cc3)c2c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc2nc(-c3ccccc3)cc(Nc3ccc(OCC4CCCCC4)cc3)c2c1

Procedure:
This compound was prepared from the corresponding 6-amino-4-(p-cyclohexylmethoxyanilino)-2-phenylquinoline with acetic anhydride, DMAP, and triethylamine in methylene chloride, followed by treatment with HCl to form the hydrochloric salt.
Reaction SMILES: [CH2:1]([Si:5]([CH:18]1[S:23][CH2:22][CH2:21][CH2:20][S:19]1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:2][CH:3]=[CH2:4].C([Li])CCC.Br[CH2:30][CH:31]([CH3:33])[CH3:32]>C1COCC1>[CH2:1]([Si:5]([C:18]1([CH2:30][CH:31]([CH3:33])[CH3:32])[S:19][CH2:20][CH2:21][CH2:22][S:23]1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:2][CH:3]=[CH2:4]
Reactant: CC(C)CBr
Reactant: C=CCC[Si](c1ccccc1)(c1ccccc1)C1SCCCS1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCC[Si](c1ccccc1)(c1ccccc1)C1(CC(C)C)SCCCS1
Reaction time: 3 h
Yield: 92.5 %

Procedure:
To a solution of 32 (4.68 g, 13.1 mmol) in THF (100 mL) at −78° C. was added dropwise over 10 min n-butyllithium (1.6 M in hexanes, 18.4 mmol). After 3 h of stirring under argon, 1-bromo-2-methylpropane (2.14 mL, 19.7 mmol) was added dropwise over 5 min, and the mixture was stirred for 2 h at 78° C. and overnight at rt. The reaction mixture was quenched with water (10 mL) and the excess organic solvent was removed under reduced pressure. The crude mixture was extracted with three 100-mL portions of EtOAc. The combined organic extracts were washed with saturated aqueous NaCl, dried over Na2SO4, and concentrated. Flash chromatography over silica gel (1/9 EtOAc:hexane) gave pure 26 as a colorless solid (5.0 g, 92%): Rf=0.75 (1/9 EtOAc:hexane); mp 67-69° C.; 1H NMR (300 MHz, CDCl3) δ 7.83 (d, J=6.0 Hz, 4H), 7.41 (m, 6H), 5.88 (m, 1H), 4.97 (dd, J=17.1, 1.7 Hz, 1H), 4.88 (dd, J=10.1, 1.7 Hz, 1H), 3.04 (m, 2H), 2.49 (t, J=4.3 Hz, 1H), 2.44 (t, J=4.1 Hz, 1H), 2.08 (d, J=5.1 Hz, 2H), 1.98 (m, 4H), 1.79 (m, 1H), 1.54 (m, 2H), 0.82 (d, J=6.7 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 141.5, 136.7, 132.9, 129.9, 127.7, 113.0, 45.7, 39.9, 28.3, 27.2, 24.6, 24.3, 24.2, 11.0; IR (film) 3068 (m), 3043 (m), 2951 (s), 2912 (s), 2863 (m), 1432 (s), 1274 (w), 1113 (s), 997 (m), 913 (m), 738 (s), 705 (s) cm−1; MS (EI) m/e (rel. intensity) 289 (M+−123, 3), 237 (8), 183 (72), 175 (100), 159 (32), 143 (17), 119 (16), 105 (35); HRMS (FAB) calcd for C24H32S2Si: 412.1715 (MH+−1), found: 412.1727. Anal. Calcd for C24H32S2Si: C, 69.84; H, 7.82. Found: C, 70.08; H, 8.07.
Reaction SMILES: Br[CH2:2][C:3]#[C:4][C@H:5]([O:11][C:12](=[O:14])[CH3:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:15]([O:18][C:19]1([C:27]#[C:28][CH2:29]Br)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)(=O)[CH3:16].C(OC1(C#CC[CH2:46][S:47]([NH:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][C:57]([O:59]CC)=[O:58])(=[O:49])=[O:48])CCCCCCC1)(=O)C>>[CH2:15]([CH:56]([CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][N:50]([CH2:2]/[CH:3]=[CH:4]/[CH:5]([O:11][C:12](=[O:14])[CH3:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[S:47]([CH3:46])(=[O:48])=[O:49])[C:57]([OH:59])=[O:58])[CH3:16].[OH:18][C:19]1([CH2:27][CH2:28][CH2:29][N:50]([CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][C:57]([OH:59])=[O:58])[S:47]([CH3:46])(=[O:49])=[O:48])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: CCOC(=O)CCCCCCNS(=O)(=O)CCC#CC1(OC(C)=O)CCCCCCC1
Reactant: CC(=O)OC1(C#CCBr)CCCCCCC1
Reactant: CCCCC[C@H](C#CCBr)OC(C)=O
Product: CCCCCC(/C=C/CN(CCCCCC(CC)C(=O)O)S(C)(=O)=O)OC(C)=O
Product: CS(=O)(=O)N(CCCCCCC(=O)O)CCCC1(O)CCCCCCC1

Procedure:
The synthesis of this compound is carried out as described in Example 3, except that, in Step A, the 1-bromo-4(R)-acetoxy-2-nonyne is replaced by an equimolar amount of 1-acetoxy-1-(3-bromo-1-propynyl)cyclooctane (Example V). The product of Step A is thus ethyl 7-{[3-(1-acetoxycyclooctyl)-2-propynyl]methanesulfonamido}heptanoate. The subsequent steps yield 7-{N-[3-(1-hydroxycyclooctyl)-2-propynyl]methanesulfonamido}heptanoic acid (B) and 7-{N-[3(1-hydroxycyclooctyl)propyl]methanesulfonamido}heptanoic acid (C).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:36][C:37]1[N:38]=[CH:39][NH:40][CH:41]=1)[C:13]([N:15]([CH2:22][C:23]([NH:25][CH2:26][C:27]([CH3:35])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:28])=[O:24])[CH2:16][CH2:17][C:18]([O:20]C)=[O:19])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.O.[OH-].[Na+]>O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:36][C:37]1[N:38]=[CH:39][NH:40][CH:41]=1)[C:13]([N:15]([CH2:22][C:23]([NH:25][CH2:26][C:27]([CH3:28])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:35])=[O:24])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCN(CC(=O)NCC(C)(C)c1ccccc1)C(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(CNC(=O)CN(CCC(=O)O)C(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
The product from Example 4 (0.30 g, 0.53 mmol) was dissolved in tetrahydrofuran (10 mL), methanol (10 mL) and water (1 mL). Sodium hydroxide (42 mg, 1.05 mmol) was added and the reaction was stirred overnight at room temperature. The solution was concentrated in vacuo and the residue taken up in 0.1 M NaPO4 buffer (100 mL). The pH was brought to 6 by the addition of 1N HCl. The product was extracted three times with ethyl acetate. The ethyl acetate was washed twice with brine, dried over MgSO4, filtered and concentrated in vacuo. Purification was carried out via reversed-phase HPLC (0.1 % trifluoroacetic acid in acetonitrile and 0.1% aqueous trifluoroacetic acid as eluent; C-18 column) to give a white powder; 0.078 g (27% yield). MS-APCI: M+1=550.3.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].C1C=CC2C(=CC=CC=2O)C=1.[Cl:23]Cl.C(N(CC)CC)C.[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>C1(C)C=CC=CC=1>[Cl:23][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:3][C:2]=1[OH:11]
Reactant: ClCl
Reactant: Oc1ccc2ccccc2c1
Reactant: C1CCNCC1
Agent: Oc1cccc2ccccc12
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Oc1cc(N2CCCCC2)c2ccccc2c1Cl
Yield: 91 %

Procedure:
2-Naphthol (28.8 g; 0.200 mol) was dissolved in toluene (210 ml) by warming. The pale brown solution was cooled and vigorously stirred until the naphthol began to precipitate and chlorine (30.20 g;0.425 mol) was then passed through the solution at approximately 2.5-3.0 g/min followed immediately by nitrogen gas. The resulting amber solution was treated firstly with triethylamine (24.68 g;0.244 mol) in one portion and then with a solution of piperidine (19.55 g;0.230 mol), in toluene (210 ml), dropwise over 1.5 hours keeping the temperature at 15°-20° C. The resulting brown mixture was filtered to remove triethylamine hydrochloride as a white amorphous solid. The toluene filtrate was washed in water, dried and evaporated to give 1-chloro-4-piperidino-2-naphthol (of structure 3a below) as a brown viscous oil (61.80 g;77% purity by gel permeation chromatography;91% yield based on 2-naphthol). Distillation gave the naphthol as a viscous amber gum B.Pt 150° C./0.3 mmHg. ##STR15## (b) 4-Piperidino-2-naphthol
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20](C2CCCCO2)[N:19]=[C:18]3[C:30]([NH:32][C:33]2[CH:34]=[N:35][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:37][CH:38]=2)=[O:31])[CH:12]=[N:13][CH:14]=1.C([SiH](CC)CC)C>C(Cl)Cl>[F:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][N:19]=[C:18]3[C:30]([NH:32][C:33]2[CH:34]=[N:35][C:36]([C:39]([F:42])([F:40])[F:41])=[CH:37][CH:38]=2)=[O:31])[CH:12]=[N:13][CH:14]=1
Reactant: O=C(Nc1ccc(C(F)(F)F)nc1)c1nn(C2CCCCO2)c2ccc(-c3cncc(F)c3)cc12
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(C(F)(F)F)nc1)c1n[nH]c2ccc(-c3cncc(F)c3)cc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 20.9 %

Procedure:
TFA (10 mL) was added to a solution of 5-(5-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)-1H-indazole-3-carboxamide (CXXX) (0.420 g, 0.86 mmol) and triethylsilane (0.345 mL, 2.16 mmol) in DCM (10 mL) and stirred 5 h at room temperature. The solvent was removed under vacuum. The residue was treated with water, sonicated briefly to disperse the solids, basified to pH 9.0 with 5 N NH4OH and sonicated again. The solids were filtered, washed with cold water and air dried at room temperature. The solids were suspended in DCM:MeOH (1:1) mixture and boiled to get a clear solution. The solution was cooled to room temperature. The solids formed were filtered washed with DCM and dried under vacuum at room temperature to get 5-(5-fluoropyridin-3-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)-1H-indazole-3-carboxamide (2) as a white solid (72.9 mg, 0.18 mmol, 21% yield). 1H NMR (DMSO-d6) δ ppm 14.13 (br. s, 1H), 11.11 (s, 1H), 9.27 (d, J=1.8 Hz, 1H), 8.84 (m, 1H), 8.63 (dd, J=6.8, 1.8 Hz, 1H), 8.60 (d, J=2.0 Hz, 1H), 8.53 (m, 1H), 8.14-8.11 (m, 1H), 7.94 (d, J=6.9 Hz, 1H), 7.90-7.83 (m, 2H); ESIMS found for C19H11F4N5O m/z 402.30 (M+H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[SH:6].Br[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:14])[CH3:13].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:14])[CH3:13]
Reactant: CC(=O)NCCCBr
Reactant: Sc1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(=O)NCCCSc1cccs1
Temperature: 23 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
A mixture of thiophene-2-thiol (1.8 g, 15.9 mmol, 1.0 eq), N-(3-bromopropyl) acetamide (4.3 g, 23.9 mmol, 1.5 eq) and K2CO3 (4.4 g, 31.8 mmol, 2.0 eq) in CH2Cl2 (50 mL) was stirred at 23° C. for 1 hour. Then the mixture was extracted with CH2Cl2. (3×). The combined organic layers were dried (Na2SO4), filtered and concentrated to give white solid N-(3-(thiophen-2-ylthio)propyl)acetamide (2.5 g, 72.8%); LC-MS (m/z)=215.9 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH:5]([O:29][CH2:30][CH3:31])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:9][CH:8]=1)C.[OH-].[Li+]>O1CCCC1.O.O>[CH2:30]([O:29][CH:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:11][CH:12]=1)[C:4]([OH:32])=[O:3])[CH3:31]
Reactant: CCOC(=O)C(Cc1ccc(OCCCCc2ccccc2OS(C)(=O)=O)cc1)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(Cc1ccc(OCCCCc2ccccc2OS(C)(=O)=O)cc1)C(=O)O
Temperature: 25 °C
Yield: 79 %

Procedure:
2-Ethoxy-3-{4-(4-(2-methanesulfonyloxyphenyl)butoxy]phenyl}propanoic acid ethyl ester (2.7 g; 5.8 mmole) was dissolved in tetrahydrofuran: water (1:3, 100 ml). Lithium hydroxide (0.36 g; 8.7 mmole) dissolved in a small amount of water was added. The reaction mixture was stirred over night at room temperature and then evaporated. The residue was redissolved in ethyl acetate and hydrochloric acid (2M) and extracted. After separation the organic phase was extracted with sodium hydroxide (1M, 30 ml). The water phase was cooled, acidified with hydrochloric acid (conc) and extracted with ethyl acetate. The organic phase was dried with magnesium sulfate and evaporation gave 2 g (79% yield) of 2-ethoxy-3-[4-(4-{2-methanesulfonyloxyphenyl}butoxy)phenyl]propanoic acid.
Reaction SMILES: [CH2:1]([C@H:8]([NH:22]C(=O)OC(C)(C)C)[C@H:9]([OH:21])[CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:30]1[CH2:35]COCC1.[ClH:36].CC[O:39]CC>>[ClH:36].[NH2:22][C@@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@H:9]([OH:21])[CH2:10][N:11]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[C:35](=[O:30])[OH:39]
Reactant: C1COCCO1
Reactant: COc1cccc(CNC[C@@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)c1
Reactant: CCOCC
Agent: Cl
Product: COc1cccc(CN(C[C@@H](O)[C@@H](N)Cc2ccccc2)C(=O)O)c1
Reaction time: 0.5 h

Procedure:
1-tert-butyl (1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propylcarbamate (XXXIV, EXAMPLE 5, 5.4 g) and dioxane-hydrochloric acid (20 ml, 4 N) are mixed. The reaction mixture is stirred at 20–25° for 30 minutes then poured into stirred ether (300 ml). The product is filtered and dried under reduced pressure to give the title compound, M+H=435.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH:6]1[CH2:9][NH:8][CH2:7]1)=[O:5].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2([C:21](O)=[O:22])[CH2:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1.C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:2][O:3][C:4]([CH:6]1[CH2:9][N:8]([C:21]([C:17]2([C:14]3[CH:13]=[CH:12][C:11]([Cl:10])=[CH:16][CH:15]=3)[CH2:18][CH2:19][CH2:20]2)=[O:22])[CH2:7]1)=[O:5]
Reactant: COC(=O)C1CNC1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CN(C(=O)C2(c3ccc(Cl)cc3)CCC2)C1
Temperature: 25 °C
Reaction time: 10 h
Yield: 70.6 %

Procedure:
To a stirred solution of azetidine-3-carboxylic acid methyl ester hydrochloride (762 mg, 4.60 mmoles) and 1-(4-chloro-phenyl)-cyclobutane carboxylic acid (2.09 g, 9.90 mmoles) in anhydrous DCM (20 mL) was added di-isopropyl ethyl amine (4.6 mL, 26.4 mmoles) dropwise. After completion of addition solid PyBroP (4.63 g, 9.94 mmoles) was added to the stirring reaction mixture. The reaction mixture continued stirring at RT for 10 h and was quenched with water. The aqueous layer was extracted with EtOAc (3×20 mL). Combined organic layers were dried over Na2SO4 and concentrated to yield an oil. This crude material was purified using silica gel chromatography (9:1 hexanes:EtOAc-1:1 hexane:EtOAc) to yield the desired amide (1.0 g, 65%). 1H NMR (300 MHz, CDCl3): δ 7.38-7.29 (m, 4H), 4.16 (m, 2H), 3.88 (m, 1H), 3.72 (s, 3H), 3.31-1.63 (m, 8H). LRMS: M+309.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:36][C:37]([O:39]C(C)(C)C)=[O:38])[C:10]([NH:12][NH:13][S:14]([NH:17][C:18]([N:20]2[CH2:23][C@H:22]([NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:21]2=[O:35])=[O:19])(=[O:16])=[O:15])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8]>CCOCC>[OH:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:36][C:37]([O:39][CH2:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=2)=[O:38])[C:10]([NH:12][NH:13][S:14]([NH:17][C:18]([N:20]2[CH2:23][C@H:22]([NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:21]2=[O:35])=[O:19])(=[O:15])=[O:16])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CC(C)(C)OC(=O)NC(C(=O)NNS(=O)(=O)NC(=O)N1C[C@H](NC(=O)OCc2ccccc2)C1=O)c1ccc(O)c(O)c1
Solvent: CCOCC
Product: O=C(NC(C(=O)NNS(=O)(=O)NC(=O)N1C[C@H](NC(=O)OCc2ccccc2)C1=O)c1ccc(O)c(O)c1)OCc1ccccc1

Procedure:
Freeze drying of the aqueous phase yielded, after stirring with ether, an additional 2.5 g of (S)-[1-[[[[2-[(3,4-dihydroxyphenyl)[[(t-butyloxy)carbonyl]amino]acetyl]hydrazino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester.