Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:32]([CH3:34])[CH3:33])[C:15]([C:17]2[CH:25]=[C:24]3[C:20]([C:21]([CH3:31])=[CH:22][N:23]3[CH2:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:19][CH:18]=2)=[O:16])[C@H:10]([CH2:35][OH:36])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.CO.CC#N.O.CC#N>O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:32]([CH3:33])[CH3:34])[C:15]([C:17]2[CH:25]=[C:24]3[C:20]([C:21]([CH3:31])=[CH:22][N:23]3[CH2:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:19][CH:18]=2)=[O:16])[C@H:10]([CH:35]=[O:36])[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COCCCn1cc(C)c2ccc(C(=O)N(C[C@@H]3CN(C(=O)OC(C)(C)C)C[C@H]3CO)C(C)C)cc21
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: COCCCn1cc(C)c2ccc(C(=O)N(C[C@@H]3CN(C(=O)OC(C)(C)C)C[C@H]3C=O)C(C)C)cc21

Procedure:
The title compound is prepared analogously as described for the title compound under I in Scheme 5 from (3S,4R)-3-hydroxymethyl-4-({isopropyl-[1-(3-methoxy-propyl)-3-methyl-1H-indole-6-carbonyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester. TLC, Rf (CH2Cl2/MeOH 95:5)=0.6. tR (HPLC, C18 column, 5-100% CH3CN/H2O/6 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 1 mL/min): 5.11 min.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=[C:12]2[N:23](CC1C=CC=CC=1)CC1C=CC=CC=1)C1C=CC=CC=1>CO.[Pd]>[NH2:23][C:12]1[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([OH:8])[CH:10]=2)[C:15]([C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccc(N(Cc2ccccc2)Cc2ccccc2)c2cc(OCc3ccccc3)ccc12
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(N)c2cc(O)ccc12
Reaction time: 20 h

Procedure:
Pd on carbon (5 wt %, 0.350 g) was added to a solution of methyl 6-(benzyloxy)-4-(dibenzylamino)-1-naphthoate (3.409 g, 6.834 mmol) in MeOH (70 mL). The system was evacuated and purged with argon and then stirred under a H2 (g) atmosphere for 20 h. The mixture was filtered through a pad of Celite and concentrated to afford methyl 4-amino-6-hydroxy-1-naphthoate as a light brown solid. MS (ESI, pos. ion) m/z: 218.1 (M+H). Mass Calc'd for C12H11NO3: 217.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]2[N:12]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[N:11]=[CH:10][C:9]=2[NH2:18])[CH:7]=1.[N:21]1[N:25]2[CH:26]=[CH:27][CH:28]=[N:29][C:24]2=[C:23]([C:30](O)=[O:31])[CH:22]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]2[N:12]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[N:11]=[CH:10][C:9]=2[NH:18][C:30]([C:23]2[CH:22]=[N:21][N:25]3[CH:26]=[CH:27][CH:28]=[N:29][C:24]=23)=[O:31])[CH:7]=1
Reactant: COc1ccc(Cl)cc1-c1c(N)cnn1CCC(C)C
Reactant: O=C(O)c1cnn2cccnc12
Agent: F[P-](F)(F)(F)(F)F
Agent: c1cnc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cl)cc1-c1c(NC(=O)c2cnn3cccnc23)cnn1CCC(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 12.3 %

Procedure:
A mixture of 5-(5-Chloro-2-methoxyphenyl)-1-isopentyl-1H-pyrazole-4-amine (573.0 mg, 1.95 mmol, 1.00 eq), pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (349.9 mg, 2.145 mmol, 1.10 eq), 7-azabenzotriazol-1-yloxy-tris-(pyrrolidino)phosphonium hexafluorophosphate (1.25 g, 2.42 mmol, 1.24 eq), and N,N-diisopropylethylamine (0.95 mL, 5.5 mmol, 2.8 eq) in 5.0 mL N,N-dimethylformamide was stirred at room temperature for 12 hours. The reaction mixture was concentrated. The crude product was purified by reverse phase HPLC and lyophilized to give 105.2 mg (12.3%) of N-(5-(5-chloro-2-methoxyphenyl)-1-isopentyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=439.1; 1H NMR (400 MHz, DMSO) δ 9.50 (s, 1H), 9.32 (dd, J=7.0, 1.6, 1H), 8.73-8.57 (m, 2H), 8.01 (s, 1H), 7.60 (dd, J=8.9, 2.7, 1H), 7.48 (d, J=2.7, 1H), 7.33 (d, J=9.0, 1H), 7.27 (dd, J=7.0, 4.2, 1H), 3.97 (dq, J=16.6, 6.8, 2H), 3.84 (s, 3H), 1.54 (q, J=7.1, 2H), 1.45-1.31 (m, 1H), 0.75 (dd, J=12.0, 6.6, 6H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:7][O:8][C:9]2[C:14]([O:15][CH3:16])=[C:13]([O:17][CH3:18])[CH:12]=[CH:11][C:10]=2[C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH2:21][CH2:22][C:23]3=[O:28])[CH2:6][O:5][CH2:4]1.C(N(CC)CC)C.[C:36](Cl)(=[O:42])[O:37][CH2:38][CH2:39][O:40][CH3:41].COC1C(OC)=CC=C(C2C=CC=C3C=2CCC3=O)C=1OCC1(CNC(=O)C)COC1>ClCCl>[CH3:41][O:40][CH2:39][CH2:38][O:37][C:36](=[O:42])[NH:1][CH2:2][C:3]1([CH2:7][O:8][C:9]2[C:10]([C:19]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:20]=3[CH2:21][CH2:22][C:23]4=[O:28])=[CH:11][CH:12]=[C:13]([O:17][CH3:18])[C:14]=2[O:15][CH3:16])[CH2:4][O:5][CH2:6]1
Reactant: COCCOC(=O)Cl
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CN)COC2)c1OC
Agent: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CNC(C)=O)COC2)c1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCOC(=O)NCC1(COc2c(-c3cccc4c3CCC4=O)ccc(OC)c2OC)COC1

Procedure:
To a stirring solution of 4-[2-(3-Aminomethyl-oxetan-3-ylmethoxy)-3,4-dimethoxy-phenyl]-indan-1-one (Compound 191) (150 mg, 0.3916 mmol) in dichloromethane (15 mL), were added triethylamine (118 mg, 1.174 mmol) and 2-methoxyethyl carbonochloridate (99 mg, 0.783 mmol) and the resultant reaction mixture was subjected to the conditions used in the preparation of Compound 192 to afford the title compound as a solid.
Reaction SMILES: Br[C:2]1[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:15][CH3:16])[CH:8]=2)[C:3]=1[O:17][CH2:18][O:19][CH3:20].[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[CH3:13][CH:12]([C:11]1[C:2]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:3]([O:17][CH2:18][O:19][CH3:20])[C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([O:15][CH3:16])=[CH:6][CH:5]=2)[CH3:14]
Reactant: COCOc1c(Br)c(C(C)C)cc2cc(OC)ccc12
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COCOc1c(-c2ccccc2)c(C(C)C)cc2cc(OC)ccc12
Temperature: 160 °C
Yield: 96.3 %

Procedure:
A sealed tube containing 2-bromo-3-(1-methylethyl)-6-(methyloxy)-1-{[(methyloxy)methyl]oxy}naphthalene (70) (0.24 g, 0.71 mmol), phenyl boronic acid (0.18 g, 1.41 mmol), Pd(PPh3)4 (82 mg, 0.07 mmol), 2 M Na2CO3 (5 mL) and DME (5 mL) was heated at 160° C. for 20 min. Cooled to room temperature, the mixture was extracted with ether (2×50 mL). The organic extracts were combined and washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a yellow oil. The crude product was purified by flash chromatography over SiO2 with hexanes:EtOAc (25:1) to give 0.23 g (97%) of compound 71 as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 1.16 (d, J=6.8 Hz, 6H), 2.92 (sept, J=6.8 Hz, 1H), 3.06 (s, 3H), 3.93 (s, 3H), 4.71 (s, 2H), 7.08-7.15 (m, 2H), 7.30-7.40 (m, 3H), 7.40-7.46 (m, 2H), 7.52 (s, 1H), 8.01 (d, J=9.0 Hz, 1H).
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[S:8][C:9]([C:13]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:14])=[C:10]([CH3:12])[N:11]=2)[C:3]1=[O:24].C(=O)([O-])[O-].[K+].[K+].[CH:31]1([CH2:34][CH2:35][NH2:36])[CH2:33][CH2:32]1>O1CCCC1.O>[CH:31]1([CH2:34][CH2:35][NH:36][CH:2]2[CH2:6][CH2:5][N:4]([C:7]3[S:8][C:9]([C:13]([NH:15][CH2:16][C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=4)=[O:14])=[C:10]([CH3:12])[N:11]=3)[C:3]2=[O:24])[CH2:33][CH2:32]1
Reactant: Cc1nc(N2CCC(Br)C2=O)sc1C(=O)NCc1ccc(F)cc1
Reactant: NCCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(N2CCC(NCCC3CC3)C2=O)sc1C(=O)NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 60 %

Procedure:
To a solution of 2-(3-bromo-2-oxopyrrolidin-1-yl)-N-(4-fluorobenzyl)-4-methylthiazole-5-carboxamide (0.050 g, 0.12 mmol) in a mixture of tetrahydrofuran and water (1/0.1, v/v) was added potassium carbonate (0.034 g, 0.24 mmol) and 2-cyclopropylethanamine (0.012 g, 0.15 mmol). The reaction mixture was stirred at ambient temperature for 17 hours and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/hexanes (3/1)) to afford the title compound as a white solid (0.030 g, 60%): mp 151-152° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.32-7.22 (m, 2H), 7.05-6.96 (m, 2H), 6.01 (t, J=5.6 Hz, 1H), 4.51 (d, J=5.6 Hz, 2H), 4.27-4.17 (m, 1H), 3.93-3.81 (m, 1H), 3.76-3.66 (m, 1H), 2.88-2.67 (m, 2H), 2.61 (s, 3H), 2.58-2.44 (m, 1H), 2.10-1.91 (m, 1H), 1.52-1.29 (m, 2H), 0.75-0.59 (m, 1H), 0.49-0.37 (m, 2H), 0.08-0.01 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 173.6, 162.3, 162.2, 155.2, 152.9, 133.7, 129.6, 118.6, 115.6, 59.5, 47.9, 44.9, 43.4, 35.0, 26.9, 17.3, 8.8, 4.4, 4.2; MS (ES+) m/z 417.3 (M+1).
Reaction SMILES: C1(CCO)CC1.[C:7]12([CH2:17][CH2:18][OH:19])[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH2:8]1)[CH2:14]2.FC1C=C(F)C(F)=CC=1C(NS(C)(=O)=O)=O.[Cl:36][C:37]1[C:38](F)=[CH:39][C:40]([F:50])=[C:41]([CH:49]=1)[C:42]([NH:44][S:45]([CH3:48])(=[O:47])=[O:46])=[O:43]>>[C:7]12([CH2:17][CH2:18][O:19][C:38]3[C:37]([Cl:36])=[CH:49][C:41]([C:42]([NH:44][S:45]([CH3:48])(=[O:47])=[O:46])=[O:43])=[C:40]([F:50])[CH:39]=3)[CH2:14][CH:13]3[CH2:12][CH:11]([CH2:10][CH:9]([CH2:15]3)[CH2:8]1)[CH2:16]2
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Reactant: OCCC12CC3CC(CC(C3)C1)C2
Agent: CS(=O)(=O)NC(=O)c1cc(F)c(F)cc1F
Agent: OCCC1CC1
Product: CS(=O)(=O)NC(=O)c1cc(Cl)c(OCCC23CC4CC(CC(C4)C2)C3)cc1F

Procedure:
Following the procedure as described in Example 1 and making variations as required to replace 2-cyclopropylethanol with 2-(adamantan-1-yl)ethanol and 2,4,5-trifluoro-N-(methylsulfonyl)benzamide with 5-chloro-2,4-difluoro-N-(methylsulfonyl)-benzamide, the title compound was obtained as a colorless solid (0.04 g, 5%): 1H NMR (300 MHz, DMSO-d6) δ 12.06 (s, 1H), 7.73 (d, J=7.5 Hz, 1H), 7.26 (d, J=12.6 Hz, 1H), 4.15 (t, J=6.9 Hz, 2H), 3.31 (s, 3H), 1.89 (br s, 3H), 1.66-1.51 (m, 14H); 13C NMR (75 MHz, DMSO-d6) δ 162.3 (d, JC-F=2 Hz), 159.9 (d, JC-F=254 Hz), 158.1 (d, JC-F=12 Hz), 130.7 (d, JC-F=4 Hz), 116.5 (d, JC-F=3 Hz), 113.6 (d, JC-F=14 Hz), 102.5 (d, JC-F=28 Hz), 66.1, 42.1, 41.8, 41.2, 36.4, 31.3, 27.9; MS (ES−) m/z 428.1, 430.1 (M−1).
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[OH-].[Na+].O.[OH:9][C:10]([CH3:24])([CH3:23])[C:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][OH:22])=[CH:15][CH:14]=1)=[O:12]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.COCCOC>[OH:9][C:10]([CH3:24])([CH3:23])[C:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][CH2:1][CH:3]2[CH2:4][O:5]2)=[CH:15][CH:14]=1)=[O:12]
Reactant: CC(C)(O)C(=O)c1ccc(OCCO)cc1
Reactant: ClCC1CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(O)C(=O)c1ccc(OCCOCC2CO2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Epichlorohydrin (24 g, 0.261 mol) is added to a mixture of 16.31 g (0.408 mol) of sodium hydroxide, 45 ml of water, and 0.761 g (2.24 mmol) of tetrabutylammonium hydrogen sulfate that is previously cooled in an ice-water bath for 20 minutes. To this mixture is added dropwise over 45 minutes with rapid stirring, a solution of 10.32 g (46.0 mmol) of 2-hydroxy-1-[4-(2-hydroxy-ethoxy)phenyl]-2-methylpropan-1-one in 95 ml of 1,2-dimethoxyethane. The reaction mixture is stirred overnight at room temperature. The aqueous layer is removed, and the organic layer is concentrated. Purification by flash chromatography on silica gel (1:1 heptane:ethyl acetate) affords 9.20 g (71% of theoretical yield) of the title compound, a pale yellow liquid.
Reaction SMILES: Cl[CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[NH:5][CH2:4]1.[N-:9]=[N+:10]=[N-:11].[Na+].[N-]=[N+]=[N-].C([N+](CCCC)(CCCC)CCCC)CCC>CC(C)=O.CN(C)C=O>[N:9]([CH2:2][C@H:3]1[O:7][C:6](=[O:8])[NH:5][CH2:4]1)=[N+:10]=[N-:11]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1NC[C@H](CCl)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: [N-]=[N+]=NC[C@@H]1CNC(=O)O1

Procedure:
5-(R)-Chloromethyloxazolidine-2-one (prepared according to [Danielmeier et al. Efficient Pathways to (R)- and (S)-hydroxymethyl-2-oxazolidinone and some derivatives. Tetrahedron: Asymmetry. 1995, vol. 6, pp. 1181-1190] (5 mmol) is reacted with sodium azide (7-10 mmol) in acetone (ca. 40-50 mL) at r.t. for ca. 24 h (until the reaction is completed). Solids are filtered off, and supernatant evaporated under vacuum to afford the product which is immediately used for the next step. Optionally, the synthesis is performed in dry N,N-dimethylformamide under inert atmosphere with sodium azide (5-10 mmol) or tetrabutylammonium azide (5-10 mmol), and the resulting solution of the crude 5-(S)-azidomethyloxazolidine-2-one is employed for the next step without solvent removal.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:19])[C:10]2[CH:11]=[CH:12][C:13]([F:18])=[C:14]([CH:17]=2)[C:15]#[N:16])[CH:5]=[C:6]([F:8])[CH:7]=1.O.C[N+]1([O-])CCOCC1>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[C:9]([C:10]1[CH:11]=[CH:12][C:13]([F:18])=[C:14]([CH:17]=1)[C:15]#[N:16])=[O:19]
Reactant: N#Cc1cc(C(O)c2cc(F)cc(F)c2)ccc1F
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: O
Solvent: ClCCl
Product: N#Cc1cc(C(=O)c2cc(F)cc(F)c2)ccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.9 %

Procedure:
A mixture of 5-[(3,5-Difluoro-phenyl)-hydroxy-methyl]-2-fluoro-benzonitrile (2.68 g, 10.2 mmol), 4-methylmorpholine N-oxide monohydrate (2.02 g, 15 mmol) and tetrapropylammonium perruthenate (35 mg, 0.1 mmol) in dry dichloromethane (50 mL) was stirred at room temperature for 2 hours. The reaction mixture was evaporated and the residue redissolved in ethyl acetate. The organic phase was washed with 10% sodium bisulphite and saturated ammonium chloride, dried and evaporated. Purification of the crude by chromatography over silica gel (EtOAc/hexane) afforded 2.05 g of the title compound (77% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:13][C@@H:14]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:15]([O:17][CH3:18])=[O:16])[C:5]([CH2:11]O)=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.S(Cl)([Cl:26])=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:13][C@@H:14]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:15]([O:17][CH3:18])=[O:16])[C:5]([CH2:11][Cl:26])=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2
Reactant: COC(=O)C[C@H](Cc1cc(Cl)c2[nH]ncc2c1CO)C(=O)OC
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)C[C@H](Cc1cc(Cl)c2[nH]ncc2c1CCl)C(=O)OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89 %

Procedure:
(S)-Dimethyl 2-((7-chloro-4-(hydroxymethyl)-1H-indazol-5-yl)methyl)succinate (2.0 g, 5.9 mmol) was dissolved in dichloromethane (35 mL). Thionyl chloride (5.0 mL) was added to the mixture. Reaction stirred at room temperature for 1.5 hours. Mixture was concentrated. Residue was dissolved in ethyl acetate. Mixture was washed twice with aqueous sodium bicarbonate and once with brine. Organic was dried (magnesium sulfate), filtered and concentrated in vacuo. Title compound was obtained as amber solid in 89% yield. MS m/e (M+H)+=359.1.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][C:18]4[C:21]([C:32]([F:35])([F:34])[F:33])=[N:22][N:23]([C:24]5[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=5)[C:17]=4[C:16]3=[O:36])=[CH:11][CH:10]=2)[CH2:8][CH2:7]1.CCN(CC)CC.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>C(Cl)Cl>[CH3:44][S:45]([N:3]1[CH2:4][CH2:5][N:1]=[C:2]1[C:6]1([C:9]2[CH:10]=[CH:11][C:12]([N:15]3[CH2:20][CH2:19][C:18]4[C:21]([C:32]([F:33])([F:34])[F:35])=[N:22][N:23]([C:24]5[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=5)[C:17]=4[C:16]3=[O:36])=[CH:13][CH:14]=2)[CH2:7][CH2:8]1)(=[O:47])=[O:46]
Reactant: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(c2ccc(C4(C5=NCCN5)CC4)cc2)CC3)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(c2ccc(C4(C5=NCCN5S(C)(=O)=O)CC4)cc2)CC3)cc1
Reaction time: 12 h

Procedure:
The product from Example 144 (0.017 g, 0.034 mmol) from was dissolved in CH2Cl2 (0.3 mL). Et3N (0.1 mL, 0.07 mmol) and MsCl (0.07 mL, 0.09 mmol) were added at rt under N2. The reaction was stirred for 12 h, concentrated to dryness, and purified via flash chromatography (silica, 100% EtOAc then 0.5% Et3N:10% MeOH:CH2Cl2) to afford the title compound. LC/MS (ESI+) 574.4 (M+H)+, tR=2.84 min (10–90% CH3CN/H2O in a 4-min run). 1H NMR ((CD3)2CO, 300 MHz) δ 7.50 (d, J=9.1 Hz, 2H), 7.33 (m, 4H), 6.98 (d, J=9.1 Hz, 2H), 4.16 (t, J=6.6 Hz, 2H), 3.83 (m, 7H), 3.16 (t, J=6.4 Hz, 2H), 2.42 (s, 3H), 1.47 (m, 2H), 1.18 (m, 2H) ppm.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[S:12][CH2:13][CH2:14][C:15]([OH:17])=O.C(N(CC)CC)C.Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>C(Cl)Cl>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH:11]1[C:5]2[CH:6]=[C:7]([NH:10][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:8]=[CH:9][C:4]=2[NH:3][C:15](=[O:17])[CH2:14][CH2:13][S:12]1
Reactant: CCOC(=O)Cl
Reactant: Nc1ccc(N)c(C(SCCC(=O)O)c2ccccc2Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Nc1ccc2c(c1)C(c1ccccc1Cl)SCCC(=O)N2
Reaction time: 1.5 h

Procedure:
A solution of 138.2 g of 3-[(2,5-diaminophenyl)(2-chlorophenyl)methylthio]propionic acid dihydrochloride in 8.6 l of dry methylene chloride is treated at -5° with 94 ml of triethylamine. Subsequently, there are successively added thereto at 0° to 2° 129.1 ml of ethyl chloroformate and 188 ml of triethylamine. The cooling means is then removed and the mixture is stirred for a further 90 minutes. The mixture is evaporated and the residue is chromatographed on 1.44 kg of silica gel. Elution is carried out with chloroform in order to remove impurities and then with chloroform/ethanol (89.5:1.5). There is obtained ethyl 6-(2-chlorophenyl)-1,3,4,6-tetrahydro-2-oxo-2H-5,1-benzothiazocine-8-carbamate of melting point 229°-231°.
Reaction SMILES: [OH-].[Li+].[C:3]([O:7][C:8]([NH:10][C@@H:11]([C:27]([O:29]C)=O)[CH2:12][S:13][CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:15][NH:16][CH2:17][CH:18]1[CH2:20][CH2:19]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.CN1CCOCC1>O1CCCC1.O.CN(C)C=O>[CH:18]1([CH2:17][N:16]2[C:27](=[O:29])[C@H:11]([NH:10][C:8](=[O:9])[O:7][C:3]([CH3:6])([CH3:4])[CH3:5])[CH2:12][S:13][C@@H:14]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:15]2)[CH2:20][CH2:19]1
Reactant: COC(=O)[C@@H](CSC(CNCC1CC1)c1ccccc1)NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1CS[C@@H](c2ccccc2)CN(CC2CC2)C1=O
Reaction time: 1 h
Yield: 31.9 %

Procedure:
Lithium hydroxide (63 mg, 1.49 mmol) was added to a solution of methyl N-(tert-butoxycarbonyl)-S-{2-[(cyclopropylmethyl)amino]-1-phenylethyl}-D-cysteinate (507 mg, 1.24 mmol) in tetrahydrofuran (10 mL) and water (2 mL). After 1 h, then mixture was concentrated and azeotroped with toluene (3×) to give the crude acid. Diphenylphosphoryl azide (0.53 ml, 2.48 mmol) was added to a solution of the crude acid and 4-methylmorpholine (0.20 mL, 1.86 mmol) in N,N-dimethylformamide (25 mL). After 4 h, the mixture was concentrated and water was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with water (2×) and saturated brine, dried over magnesium sulfate, filtered, and concentrated. Purification by silica gel chromatography (5% ethyl acetate/hexanes→20% ethyl acetate/hexanes) gave the title compound (149 mg). MS 377 (M+1).
Reaction SMILES: [CH:1]1([Sn](CCCC)(CCCC)CCCC)[CH2:3][CH2:2]1.C([Li])CCC.[Cl:22][C:23]1[N:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>C1COCC1.[Cu]I>[CH:1]1([C:25]([C:24]2[C:23]([Cl:22])=[N:31][CH:30]=[CH:29][CH:28]=2)=[O:26])[CH2:3][CH2:2]1
Reactant: CCCC[Sn](CCCC)(CCCC)C1CC1
Reactant: O=C(Cl)c1cccnc1Cl
Agent: [Cu]I
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(c1cccnc1Cl)C1CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
A mixture of cyclopropyltributyltin (0.5 g, 1.51 mmol) in 3 mL of THF was cooled to -78° C. and then n-butyllithium (0.604 mL, 2.5M in hexanes, 1.51 mmol) was added. The mixture was stirred at 0° C. for 0.5 hours. A mixture of copper(I) iodide (0.142 g, 0.75 mmol) in THF was cooled to -40° C. and the mixture containing the cyclopropyltributyltin was added. The mixture was stirred for 45 minutes and then 2-chloronicotinic acid chloride (0.265 g, 1.51 mmol) was added dropwise. The mixture was stirred at -40° C. for 1.5 hours and allowed to warm to room temperature. The mixture was quenched with water, diluted with methylene chloride, filtered and the aqueous layer was extracted with methylene chloride (2×30 mL). The combined organic layers were dried (Na2SO4) and concentrated. The residue was purified on silica gel by flash chromatography eluting with hexanes/ethyl acetate (85:15) to give 2-chloro-3-pyridyl cyclopropyl ketone (0.15 g, 0.83 mmol) as an oil.
Reaction SMILES: [O:1]=[C:2]1[N:8]2[C@H:4]([CH2:5][C:6]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][Si](C)(C)C)[CH:23]=3)=[C:7]2[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[O:10])[C@H:3]1[C@H:33]([O:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH3:34].C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.C(=O)([O-])O.[Na+]>C1COCC1.C(OCC)(=O)C>[OH:28][C:24]1[CH:23]=[C:22]([C:6]2[CH2:5][C@H:4]3[N:8]([C:2](=[O:1])[C@@H:3]3[C@H:33]([O:35][Si:36]([CH3:38])([CH3:39])[CH3:37])[CH3:34])[C:7]=2[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[O:10])[CH:27]=[CH:26][CH:25]=1
Reactant: C[C@@H](O[Si](C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cccc(O[Si](C)(C)C)c3)C[C@H]12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: C[C@@H](O[Si](C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cccc(O)c3)C[C@H]12
Reaction time: 0.25 h

Procedure:
To a solution of 4-nitrobenzyl (5R,6S)-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-3-{3-[(trimethylsilyl)oxy]phenyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (500 mg) in THF (8.6 ml) was added at −78° C. acetic acid (51 mg). Thereto was dropped 1M tetrabutylammonium fluoride/THF solution (0.86 ml), and the mixture was stirred at the same temperature for 15 minutes. The reaction mixture was poured into a mixture of a cold aqueous sodium hydrogencarbonate (72 mg) and ethyl acetate. The mixture was extracted and separated by a separating funnel. The organic layer was washed with a cold saturated aqueous sodium chloride solution (three times) and cold water in the order, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 4-nitrobenzyl (5R,6S)-3-(3-hydroxyphenyl)-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate. This product was used in the next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][N:28]2[CH2:32][CH2:31][NH:30][C:29]2=[O:33])=[O:24])[C:5]1=[O:34].[N:35]1([C:41](Cl)=[O:42])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][C:11]2[CH:12]=[C:13]3[C:8]([C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][N:28]4[CH2:32][CH2:31][NH:30][C:29]4=[O:33])=[O:24])[C:5](=[O:34])[N:4]3[CH2:3][CH2:2][NH:1][C:41]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[O:42])=[N:9][CH:10]=2)=[CH:20][CH:19]=1
Reactant: NCCn1c(=O)c(C(=O)NCCN2CCNC2=O)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Reactant: O=C(Cl)N1CCOCC1
Product: O=C(NCCN1CCNC1=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCNC(=O)N2CCOCC2)c1=O

Procedure:
This compound was prepared from 1-(2-aminoethyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-N-[2-(2-oxo-1-imidazolidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxamide and 4-morpholinecarbonyl chloride employing methods similar to those described in Example 450 and was obtained as an orange solid: ES+ MS: 582 (M+H+).