Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:26][CH2:25][C:5]2[N:6]([CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[N:21][CH:22]=3)[OH:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-:27].[K+]>C(O)(C)(C)C>[CH3:1][N:2]1[CH2:26][CH2:25][C:5]2[N:6]([CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([NH2:24])=[O:27])=[N:21][CH:22]=3)[OH:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(O)c2ccc(C#N)nc2)CCN(C)C1
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: Cc1ccc2c(c1)c1c(n2CC(O)c2ccc(C(N)=O)nc2)CCN(C)C1
Temperature: 80 °C
Reaction time: 1 h
Yield: 12.8 %

Procedure:
To a solution of 5-[2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-hydroxy-ethyl]-pyridine-2-carbonitrile (1.5 g, 4.3 mmol) in tert-butanol (30 mL) was added crushed KOH (728 mg, 13 mmol) and the reaction mixture was stirred at 80° C. for 1 h. The progress of reaction was monitored by LCMS. The reaction mixture was concentrated. The residue was diluted with water (50 mL) and extracted with EtOAc (2×100 mL). The combined organic layer was washed with water (2×100 mL), dried over anhydrous sodium sulfate and concentrated. The crude material was purified by reverse phase HPLC to yield 5-[2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-hydroxy-ethyl]-pyridine-2-carboxylic acid amide (200 mg). 1H NMR (CDCl3, freebase) δ (ppm): 8.45 (d, 1H), 8.12 (t, 1H), 7.78 (s, 2H), 7.05 (m, 2H), 6.94 (t, 1H), 5.57 (bs, 1H), 5.03 (m, 1H), 4.13 (s, 2H), 3.63 (m, 2H), 2.79 (m, 2H), 2.78 (bs 1H), 2.66 (d, 1H), 2.53 (d, 3H), 2.42 (s, 3H). Separation by chiral HPLC provided enantiomers 144a and 144b.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[C:17]([C:31](=[O:33])[NH2:32])[N:18]3[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[C:17]([C:31](=[O:33])[NH2:32])[N:18]3[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc3c2cc(C(N)=O)n3Cc2cccc(F)c2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2cccc3c2cc(C(N)=O)n3Cc2cccc(F)c2)CC1
Reaction time: 8 h
Yield: 48.1 %

Procedure:
4-[2-Carbamoyl-1-(3-fluoro-benzyl)-1H-indol-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (156 mg, 0.35 mmol) in EtOH (20 ml) was added to a Parr vessel containing catalytic amount of 5% Pd on carbon. The vessel was purged with H2 at the pressure of 50 psi (3.45 bar). After shaking overnight, the reaction mixture was filtered through Celite and concentrated. The brown residue was purified by flash chromatography to give 4-[2-carbamoyl-1-(3-fluoro-benzyl)-1H-indol-4-yl]-piperidine-1-carboxylic acid tert-butyl ester as yellow solid (76 mg, 48%).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][N:10]2[CH2:17][CH2:16][C:13]3([CH2:15][CH2:14]3)[CH2:12][CH:11]2[C:18]([NH:20][C:21]2([C:24]3[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=3)[CH2:23][CH2:22]2)=[O:19])=[CH:5][CH:4]=1.[Li+].[OH-]>>[F:35][C:2]([F:1])([F:34])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][N:10]2[CH2:17][CH2:16][C:13]3([CH2:15][CH2:14]3)[CH2:12][CH:11]2[C:18]([NH:20][C:21]2([C:24]3[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)[CH2:22][CH2:23]2)=[O:19])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(C2(NC(=O)C3CC4(CCN3Cc3ccc(C(F)(F)F)nc3)CC4)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)c1ccc(C2(NC(=O)C3CC4(CCN3Cc3ccc(C(F)(F)F)nc3)CC4)CC2)cc1
Yield: 76.7 %

Procedure:
The title compound (E8) (35 mg) was prepared according to the general procedure for esters hydrolysis (Method D) starting from methyl 4-(1-(6-((6-(trifluoromethyl)pyridin-3-yl)methyl)-6-azaspiro[2.5]octane-5-carboxamido)cyclopropyl)benzoate (D124) (47 mg). (LiOH: 4 eq; Reaction time: 5 hrs; RT)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:4]=1[O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1>ClCCl.CO>[CH3:1][O:2][C:3]1[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:4]=1[O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: COc1cc([N+](=O)[O-])ccc1OCCN1CCOCC1
Solvent: CO
Solvent: ClCCl
Product: COc1cc(N)ccc1OCCN1CCOCC1

Procedure:
Prepared analogously to Example 3.1.b. from 4-[2-(2-methoxy-4-nitrophenoxy)ethyl]morpholine. Yield: 0.23 g (85.8% of theory); C13H20N2O3 (M=252.31); calc.: molecular ion peak (M+H)+: 253; found: molecular ion peak (M+H)+: 253; Rf value: 0.5 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][C:37]1([CH3:43])[CH3:42]>>[F:34][C:2]([F:33])([F:1])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:39]4[CH2:40][CH2:41][N:36]([CH3:35])[C:37]([CH3:43])([CH3:42])[CH2:38]4)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: CN1CCNCC1(C)C
Product: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CC1(C)C

Procedure:
5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-(3,3,4-trimethylpiperazin-1-yl)-1,3-thiazol-4(5H)-one was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 1,2,2-Trimethyl-piperazine following General Procedure C.
Reaction SMILES: [CH2:1]([O:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Br[CH2:26][C:27]([O:29][CH3:30])=[O:28].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>C(Cl)(Cl)Cl>[CH3:30][O:29][C:27](=[O:28])[CH2:26][O:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:19][CH:20]=1
Reactant: COC(=O)CBr
Reactant: CCCCCCCCCCCCCCCCOc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCOc1ccc(OCC(=O)OC)cc1
Yield: 89.4 %

Procedure:
A mixture of 23 g of product from Example 84, 13.15 g of methyl bromoacetate, 10.45 g of potassium carbonate and 200 ml of acetone is heated at reflux for 24 hours. The reaction is cooled, chloroform added, filtered and concentrated. The residue is recrystallized from hexane to give 25 g of the desired product as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([CH2:14][O:15][Si](C(C)(C)C)(C)C)[CH2:12][O:11][C@H:10]([O:23][CH2:24][CH3:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([CH2:14][OH:15])[CH2:12][O:11][C@H:10]([O:23][CH2:24][CH3:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCO[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCO[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](CO)CO1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 92.7 %

Procedure:
Dissolve (2S,5R)-5-(tert-butyldimethylsilanyloxymethyl)-2-ethoxymorpholine-4-carboxylic acid tert-butyl ester (0.39 g, 1.04 mmole) in tetrahydrofuran (3 mL) and add tetrabutylammonium fluoride (2.1 mL, 2.1 mmol, 1.0 M in tetrahydrofuran). Stir 45 minutes at room temperature, concentrate and purify (silica gel chromatography, eluting with 10:90 to 40:60 ethyl acetate:hexanes) to give the desired compound (252 mg, 92%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[C:10](Br)=[CH:9][C:8]([C:12]2[C:17]([CH2:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:20][CH3:21])=[N:7][C:6]=1[CH3:22])[CH3:2].[C:24]([Si:28]([O:31][C:32]([CH3:36])([CH3:35])[C:33]#[CH:34])([CH3:30])[CH3:29])([CH3:27])([CH3:26])[CH3:25]>C(NC(C)C)(C)C.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.[Cu](I)I>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[C:10]([C:34]#[C:33][C:32]([O:31][Si:28]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:30])[CH3:29])([CH3:36])[CH3:35])=[CH:9][C:8]([C:12]2[C:17]([CH2:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:20][CH3:21])=[N:7][C:6]=1[CH3:22])[CH3:2]
Reactant: CCOC(=O)c1c(Br)cc(-c2c(CC)cccc2CC)nc1C
Reactant: C#CC(C)(C)O[Si](C)(C)C(C)(C)C
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)c1c(C#CC(C)(C)O[Si](C)(C)C(C)(C)C)cc(-c2c(CC)cccc2CC)nc1C
Temperature: 105 °C

Procedure:
A mixture of 4-bromo-6-(2,6-diethyl-phenyl)-2-methyl-nicotinic ethyl ester (274 mg, 0.73 mmol), tert-butyl-(1,1-dimethyl-prop-2-ynyloxy)-dimethyl-silane (724 mg, 0.37 mmol), Pd(PPh3)4 (84 mg, 0.082 mmol), and copper iodide (7 mg, 0.037 mmol) in diisopropylamine (8 mL) is heated at 105° C. in a scaled tube. The filtrate is concentrated in vacuo. The residue is purified by flash chromatography to give 4-[3-(tert-butyl-dimethyl-silanyloxy)-3-methyl-but-1-ynyl]-6-(2,6-diethyl-phenyl)-2-methyl-nicotinic acid ethyl ester as a pale yellow oil. 1H NMR (CDCl3) 7.38-7.31 (m, 2H), 7.17-7.12 (m, 2H), 4.43 (q, 2H), 2.62 (s, 3H), 2.38-2.25 (m, 4H), 1.56 (s, 6H), 1.44 (t, 3H), 1.06 (t, 6H), 0.83 (s, 9H), 0.15 (s, 6H).
Reaction SMILES: [CH2:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)[CH:2]=[CH2:3].[I:9]N1C(=O)CCC1=O.C([O-])(O)=O.[Na+]>C1COCC1>[I:9][CH2:3][CH2:2][CH2:1][C:4]1[S:5][CH:6]=[CH:7][CH:8]=1
Reactant: C=CCc1cccs1
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: ICCCc1cccs1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 61.4 %

Procedure:
Cp2ZrHCl (9.141 g, 35.4 mmol) was added to a solution of 33 (3.668 g, 29.5 mmol) in THF (50 mL). The mixture was stirred for 1.5 h at 40° C., cooled to 0° C. and was then treated with N-iodosuccinimide (NIS, 7.972 g, 35.4 mmol). The reaction was allowed to warm to room temperature and after 75 min., 100 mL of saturated NaHCO3 solution was added. The mixture was extracted with ether (2×100 mL) and the combined ether solution was dried (Na2SO4), filtered and evaporated. The residue was purified on a Teledyne Isco Combiflash unit (330 g silica gel column, 0%→20% ethyl acetate/hexanes) which gave the title compound (4.558 g, 18.1 mmol, 61%).
Reaction SMILES: [CH2:1]([N:9]1[CH2:13][CH2:12][CH2:11][C:10]1=[O:14])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.S(=O)(=O)(O)O.II.[I:22](O)(=O)(=O)=O>C(O)(=O)C.O>[I:22][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][CH2:1][N:9]2[CH2:13][CH2:12][CH2:11][C:10]2=[O:14])=[CH:4][CH:5]=1
Reactant: [O-][I+3]([O-])([O-])O
Reactant: O=C1CCCN1CCc1ccccc1
Agent: II
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C1CCCN1CCc1ccc(I)cc1
Temperature: 60 °C

Procedure:
To a stirring solution of HJC-1-53 (500 mg, 2.6 mmol), water (1 mL), 95% sulfuric acid (285 mg, 2.9 mmol) and acetic acid (8 mL) was added iodine (335 mg, 1.3 mmol) and periodic acid (H5IO6, 150 mg, 0.7 mmol) at rt. The reaction mixture was warmed to 60° C. for 3 h. After cooling down to rt, the solution was extracted with EtOAc (80 mL) and H2O (20 mL), and washed with 10% NaHSO3 (20 mL), followed by 10% NaHCO3 (40 mL). The organic layer was separated and washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to give an oil residue. This residue was purified with silica gel column (Hexane/EtOAc=1/2) to obtain HJC-1-60 (130 mg, 16%) as a pale yellow oil. 1H NMR (600 MHz, CDCl3) δ 7.60 (d, 1H, J=7.8 Hz), 7.26-7.30 (m, 1H), 7.19-7.21 (m, 1H), 6.96 (d, 1H, J=9.0 Hz), 3.48-3.53 (m, 2H), 3.23-3.26 (m, 2H), 2.83 (t, 1H, J=7.8 Hz), 2.78 (t, 1H, J=7.8 Hz), 2.32-2.36 (m, 2H), 1.91-1.97 (m, 2H).
Reaction SMILES: [CH:1]1([CH2:6][O:7][NH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([F:28])=[C:23]([CH:27]=2)[C:24]([OH:26])=O)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[CH:1]1([CH2:6][O:7][NH:8][C:9](=[O:10])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([F:28])=[C:23]([C:24]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:26])[CH:27]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1cc(CNc2ccccc2C(=O)NOCC2CCCC2)ccc1F
Reactant: C1COCCN1
Product: O=C(NOCC1CCCC1)c1ccccc1NCc1ccc(F)c(C(=O)N2CCOCC2)c1

Procedure:
Prepared by a similar procedure as described for the preparation of Example 499, starting from 5-[(2-cyclopentylmethoxycarbamoyl-phenylamino)methyl]-2-fluoro-benzoic acid (Example 496) and morpholine.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH3:44])[CH2:30][CH2:31][N:32]([C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][C:37]=1[Br:43])[C:33](=[O:35])[CH3:34]>>[CH3:44][N:29]([CH3:28])[CH2:30][CH2:31][N:32]([C:36]1[CH:42]=[CH:41][C:39]([NH:40]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:38][C:37]=1[Br:43])[C:33](=[O:35])[CH3:34]
Reactant: CC(=O)N(CCN(C)C)c1ccc(N)cc1Br
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(CCN(C)C)C(C)=O)c(Br)c1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(N-(2-dimethylamino-ethyl)-N-acetyl-amino)-3-bromo-aniline Rf value: 0.6 (silica gel, methylene chloride/methanol=5:1) C29H29BrN4O4
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@H:11]3[C:15]4([CH2:18][CH2:17][CH2:16]4)[CH2:14][N:13]([C:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:20])[CH2:12]3)=[C:8]([C:29](=[O:31])[NH2:30])[CH:7]=[N:6][N:5]2[CH:32]=1.[CH3:33][N:34]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[N:35]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].N#N>O1CCOCC1.CCOCC>[C:29]([C:8]1[CH:7]=[N:6][N:5]2[CH:32]=[C:2]([C:37]3[CH:36]=[N:35][N:34]([CH3:33])[CH:38]=3)[CH:3]=[C:4]2[C:9]=1[NH:10][C@H:11]1[C:15]2([CH2:18][CH2:17][CH2:16]2)[CH2:14][N:13]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:12]1)(=[O:31])[NH2:30]
Reactant: NC(=O)c1cnn2cc(Br)cc2c1N[C@@H]1CN(C(=O)OCc2ccccc2)CC12CCC2
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: N#N
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cn1cc(-c2cc3c(N[C@@H]4CN(C(=O)OCc5ccccc5)CC45CCC5)c(C(N)=O)cnn3c2)cn1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 103.3 %

Procedure:
A solution of (S)-benzyl 8-((6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-6-azaspiro[3.4]octane-6-carboxylate (120.0 mg, 0.241 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (100 mg, 0.482 mmol) in 1,4-dioxane (3.20 mL) and potassium phosphate (2.0M) (0.361 mL, 0.722 mmol) was degassed for several minutes with N2 gas. 1,1′-Bis(diphenylphosphino)ferrocenepalladium(II) dichloride dichloromethane complex (19.81 mg, 0.024 mmol) was added, degassing was continued for 1 more minute, vial was sealed, and the contents were heated @ 110° C. for 45 minutes. HPLC and LC/MS after 30 min indicated that the reaction had essentially proceeded to completion (m/e 500.16, M+H for desired product). After cooling to r. t., the reaction was diluted with EtOAc and water. The layers were separated, the EtOAc layer was washed with water, brine, dried over Na2SO4, and concentrated under vacuum to yield a solid. Trituration with ether yielded 124.4 mg of the title compound as a pale mustard-colored solid. LC/MS: m/e 500.15 (M+H). This material was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C@@H:13]([CH3:16])[CH2:14][OH:15])[CH2:8]1.O[C:21]1[CH:53]=[CH:52][C:24]([CH2:25][CH:26]2[S:30][C:29](=[O:31])[N:28]([C:32]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]2=[O:51])=[CH:23][CH:22]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C@@H:13]([CH3:16])[CH2:14][O:15][C:21]2[CH:53]=[CH:52][C:24]([CH2:25][CH:26]3[S:30][C:29](=[O:31])[N:28]([C:32]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:27]3=[O:51])=[CH:23][CH:22]=2)[CH2:8]1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[C@@H](CO)N1C[C@H](COc2cccc(Cl)c2)OC1=O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Product: C[C@@H](COc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)N1C[C@H](COc2cccc(Cl)c2)OC1=O
Yield: 66.9 %

Procedure:
A procedure similar to that described in Preparation 6 was repeated, except that 0.46 g of 2(S)-[5(R)-(3-chlorophenoxymethyl)-2-oxooxazolidin-3-yl]propanol (prepared as described in Preparation 36), 0.90 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 0.39 g of tributylphosphine, 0.49 g of azodicarbonyldipiperidine and 30 ml of anhydrous benzene were used, to give 0.79 g of the title compound having an Rf value of 0.26 (on silica gel thin layer chromatography, using a 1:1 by volume mixture of ethyl acetate and hexane as the developing solvent) and having [α]D =-35.3° (methanol, c=1.015).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([N:5]([CH3:17])[C:6]1[S:10][C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:8][CH:7]=1)=[O:4].[Cl:20]N1C(=O)CCC1=O>C(#N)C>[Cl:20][C:7]1[N:8]=[C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[S:10][C:6]=1[N:5]([CH3:17])[C:3](=[O:4])[C:2]([F:18])([F:1])[F:19]
Reactant: CN(C(=O)C(F)(F)F)c1cnc(-c2cccnc2)s1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CN(C(=O)C(F)(F)F)c1sc(-c2cccnc2)nc1Cl
Temperature: 63 °C

Procedure:
A suspension of 2,2,2-trifluoro-N-methyl-N-(2-pyridin-3-yl-thiazol-5-yl)-acetamide (1.0 g, 3.5 mmol) and N-chlorosuccinimide (0.557 g, 4.2 mmol) in acetonitrile (30 mL) was heated to 63° C. under nitrogen for 3 h. The reaction mixture was cooled to room temperature and it was treated with additional N-chlorosuccinimide (0.557 g, 4.2 mmol) and heated to 35° C. under nitrogen for 2 h. The reaction mixture was cooled and concentrated under reduced pressure. The residue was redissolved in dichloromethane (80 mL) and washed with water (70 mL). The aqueous layer was re-extracted with methylene chloride (100 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure and purified using reverse phase chromatography. The product eluted with a gradient of acetonitrile in water. The desired product was isolated as a thick brown gum (0.337 g, 30%): 1H NMR (400 MHz, CDCl3) δ 9.12 (br, 1H), 8.75 (br, 1H), 8.22 (d, J=7.9 Hz, 1H), 7.28 (br, 1H), 3.40 (s, 3H); 19F NMR (376 MHz, CDCl3) δ−69.3; ESIMS m/z 324.3 (M+2); IR (thin film) 1772 cm−1.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[C:23]([NH:26][NH:27][C:28]([C@@H:30]1[CH2:35][CH2:34][CH2:33][CH2:32][N:31]1[S:36]([C:39]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=1)(=[O:38])=[O:37])=O)(=O)[CH3:24]>C1(C)C=CC=CC=1>[F:45][C:42]1[CH:43]=[CH:44][C:39]([S:36]([N:31]2[CH2:32][CH2:33][CH2:34][CH2:35][C@H:30]2[C:28]2[S:10][C:23]([CH3:24])=[N:26][N:27]=2)(=[O:38])=[O:37])=[CH:40][CH:41]=1
Reactant: CC(=O)NNC(=O)[C@@H]1CCCCN1S(=O)(=O)c1ccc(F)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Cc1nnc([C@@H]2CCCCN2S(=O)(=O)c2ccc(F)cc2)s1

Procedure:
Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulphide] (271 mg) was added to a solution of N′2-acetyl-(2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidinecarbohydrazide (192 mg) [see Preparation 39] in toluene (10 ml). The reaction mixture was heated under reflux for 3 hours and the cooled mixture was then purified by column chromatography on silica gel eluting with a solvent gradient of 0:100 changing to 30:70 (in 10% increments), by volume, hexane:ethyl acetate, to afford 2-[(2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidyl]-5-methyl-1,3,4-thiadiazole (106 mg) as a clear oil.
Reaction SMILES: S(Cl)([Cl:3])=O.[O:5]1[CH2:9][CH2:8][N:7]=[C:6]1[C:10]1[CH:31]=[CH:30][C:13]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]2[O:26][N:25]=[C:24]([CH3:27])[C:23]=2[CH2:28]O)=[CH:12][CH:11]=1>C(Cl)Cl>[Cl:3][CH2:28][C:23]1[C:24]([CH3:27])=[N:25][O:26][C:22]=1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][O:14][C:13]1[CH:30]=[CH:31][C:10]([C:6]2[O:5][CH2:9][CH2:8][N:7]=2)=[CH:11][CH:12]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1noc(CCCCCCCOc2ccc(C3=NCCO3)cc2)c1CO
Solvent: ClCCl
Product: Cc1noc(CCCCCCCOc2ccc(C3=NCCO3)cc2)c1CCl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 2.1 ml of thionyl chloride in 5.0 ml of methylene dichloride cooled in an ice-bath was added over a 30 minute period a suspension of 5 g of 5-{7-[4-(4,5-dihydro-2-oxazolyl)phenoxy]heptyl}-3-methyl-4-isoxazolemethanol (Example 29) in 20 ml of methylene dichloride. The reaction mixture was stirred at 0° C. for 2 hours and then at room temperature for 3 hours. The solvent was then removed in vacuo and the residue triturated with ether. The solid product was collected and recrystallized from acetonitrile to give 4.5 g of 4-chloromethyl-5-{7-[4-(4,5-dihydro-2-oxazolyl)phenoxy]heptyl}-3-methylisoxazole in the form of its monohydrochloride salt, tan solid, m.p. 103°-104° C.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[Cl-].[Al+3].[Cl-].[Cl-].[C:10]1([CH:16]([CH3:18])[CH3:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>C(=S)=S>[CH:16]([C:10]1[CH:15]=[CH:14][C:13]([C:1](=[O:4])[CH2:2][CH3:3])=[CH:12][CH:11]=1)([CH3:18])[CH3:17]
Reactant: CC(C)c1ccccc1
Reactant: CCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: S=C=S
Product: CCC(=O)c1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 112.1 %

Procedure:
Propionyl chloride (11.6 g, 125 mmol) was dropwise added to a suspension of aluminium chloride (16.7 g, 125 mmol) and cumene (18.0 g, 150 mmol) in carbon disulfide (30 mL) at −5° C., and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was poured into water with ice, and the organic layer was separated, washed with an aqueous saturated sodium hydrogencarbonate and water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 1-(4-isopropylphenyl)propan-1-one (24.7 g). Sodium borohydride (1.29 g, 34.2 mmol) was added to a solution of the thus-obtained compound (13.0 g, 68.4 mmol) in ethanol (80 mL) with cooling with ice, and the mixture was stirred for 30 minutes at room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (11.5 g, yield 79%). This was oily.