Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:37])([CH3:36])[C:3]([N:5]1[N:9]=[C:8]([NH:10][C:11](=[O:20])[CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[S:7][C:6]1([CH2:27][CH2:28][CH2:29][C:30]([NH:32][CH2:33][CH2:34][OH:35])=[O:31])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:4].N1C=CC=CC=1.[Si:44](Cl)([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45].Cl>O.ClCCl>[O:35]([CH2:34][CH2:33][NH:32][C:30](=[O:31])[CH2:29][CH2:28][CH2:27][C:6]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:5]([C:3](=[O:4])[C:2]([CH3:36])([CH3:1])[CH3:37])[N:9]=[C:8]([NH:10][C:11](=[O:20])[CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[S:7]1)[Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C(=O)NC1=NN(C(=O)C(C)(C)C)C(CCCC(=O)NCCO)(c2ccccc2)S1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CC(C(=O)NC1=NN(C(=O)C(C)(C)C)C(CCCC(=O)NCCO[Si](C)(C)C(C)(C)C)(c2ccccc2)S1)c1ccccc1
Temperature: 0 °C
Yield: 84.7 %

Procedure:
To 4-[3-(2,2-dimethylpropionyl)-2-phenyl-5-(2-phenylpropionylamino)-2,3-dihydro-1,3,4-thiadiazol-2-yl]-N-(2-hydroxyethyl)butanamide (1.21 g, 2.31 mmol) obtained in Step 4 mentioned above was added dichloromethane (20 mL), and the mixture was stirred at 0° C. Then, to the mixture were added pyridine (0.470 mL, 5.77 mmol) and tert-butyldimethylsilyl chloride (869 mg, 5.77 mmol), and the mixture was stirred at room temperature for 3 hours. To the mixture were added 1 mol/L hydrochloric acid (20 mL) and water (30 mL), and the mixture was extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To the resulting residue was added diisopropyl ether, and the deposited white solid was collected by filtration. The resulting solid was washed with water and diisopropyl ether, and dried under reduced pressure to give N-[2-(tert-butyldimethylsiloxy)ethyl]-4-[3-(2,2-dimethylpropionyl)-2-phenyl-5-(2-phenylpropionylamino)-2,3-dihydro-1,3,4-thiadiazol-2-yl]butanamide (1.25 g, 85%).
Reaction SMILES: [Br:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([OH:13])=[C:7]([CH3:14])[C:3]=1[C:4]([OH:6])=[O:5].[C:15]([Si:19]([CH3:22])([CH3:21])Cl)([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>C(#N)C>[Br:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([O:13][Si:19]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:22])[CH3:21])=[C:7]([CH3:14])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1cc(O)c(C)c(C(=O)O)c1Br
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1cc(O[Si](C)(C)C(C)(C)C)c(C)c(C(=O)O)c1Br
Temperature: 20 °C
Reaction time: 16 h
Yield: 69.6 %

Procedure:
To a solution of 12.0 g of 2-bromo-5-hydroxy -3-methoxy-6-methyl-benzoic acid in 700 ml of acetonitrile were added at -5° C. 27.7 g of tert-butyldimethylchlorosilane and 18.5 g of triethylamine. The mixture was stirred for 30 min at -5° C. and for 16 h at 20° C. The solvent was evaporated in vacuo and the solid residue was washed with water and dried in vacuo. A solution of this material in 200 ml of ethanol was heated for 8 h to 80° C. The solvent was evaporated in vacuo and the residue was recrystallized from pentane to yield 12.0 g of 2-bromo-5-(tert-butyl-dimethylsilanyloxy)-3-methoxy-6-methyl-benzoic acid as white crystals, m.p. 120°-125° C.
Reaction SMILES: S(O[CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)(C1C=CC(C)=CC=1)(=O)=O.BrCC1CCCCO1.[NH:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]2([C:54]3[C:45](=[CH:46][C:47]4[O:52][CH2:51][CH2:50][O:49][C:48]=4[CH:53]=3)[O:44][CH2:43]2)[C:35]1=[O:55]>>[O:55]=[C:35]1[C:36]2([C:54]3[C:45](=[CH:46][C:47]4[O:52][CH2:51][CH2:50][O:49][C:48]=4[CH:53]=3)[O:44][CH2:43]2)[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:34]1[CH2:12][CH:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:17][CH2:18]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: BrCC1CCCCO1
Product: CC(C)(C)OC(=O)N1CCC(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)CC1

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using tert-butyl 4-(tosyloxymethyl)piperidine-1-carboxylate to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, tert-butyl 4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]piperidine-1-carboxylate was obtained (99%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.34-7.26 (m, 1H), 7.14-7.19 (m, 1H), 7.08-7.01 (m, 1H), 6.88 (d, J=7.8 Hz, 1H), 6.50 (s, 1H), 6.19 (s, 1H), 4.87 (d, J=9.0 Hz, 1H), 4.62 (d, J=9.0 Hz, 1H), 4.23-4.06 (m, 6H), 3.80-3.44 (m, 2H), 2.76-2.59 (m, 2H), 2.11-1.93 (m, 1H), 1.74-1.60 (m, 2H), 1.45 (s, 9H), 1.37-1.20 (m, 2H).
Reaction SMILES: [OH:1][CH:2]([C:7]1[S:8][C:9]2[CH:15]=[C:14]([N:16]3[CH2:20][CH:19]([CH2:21][O:22][CH3:23])[O:18][C:17]3=[O:24])[CH:13]=[CH:12][C:10]=2[N:11]=1)[CH2:3][CH2:4][CH2:5]O.[CH2:25]([N:27](CC)CC)C.CS(Cl)(=O)=O.C(OCC)C>C(Cl)Cl>[OH:1][CH:2]([C:7]1[S:8][C:9]2[CH:15]=[C:14]([N:16]3[CH2:20][CH:19]([CH2:21][O:22][CH3:23])[O:18][C:17]3=[O:24])[CH:13]=[CH:12][C:10]=2[N:11]=1)[CH2:3][CH2:4][CH2:5][C:25]#[N:27]
Reactant: COCC1CN(c2ccc3nc(C(O)CCCO)sc3c2)C(=O)O1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: CCOCC
Solvent: ClCCl
Product: COCC1CN(c2ccc3nc(C(O)CCCC#N)sc3c2)C(=O)O1
Reaction time: 0.5 h

Procedure:
2.8 g of the 3-[2-(1,4-dihydroxybutyl)benzothiazol-6-yl]-5-methoxymethyl-2-oxazolidinone thus obtained was dissolved in 20 ml of anhydrous methylene chloride and 1 ml of anhydrous triethylamine was added to the solution. 0.6 ml of methanesulfonyl chloride was slowly added to the solution under cooling with ice. After stirring for 30 min, 100 ml of diethyl ether was added to the reaction mixture. An insoluble matter was filtered off and then the solvent was distilled off. The resulting crude product was dissolved in 15 ml of dimethyl sulfoxide. 1.5 g of potassium cyanide was added to the solution and a reaction was conducted at 80° C. for 8 h. After cooling the reaction liquid followed by ordinary treatment and purification, 1.5 g of the titled compound was obtained.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:19]=[C:20]([OH:22])[CH:21]=2)[C:10]([NH:12][C:13]2[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=2)=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:23]1([C:27]([C:29]2[CH:34]=[CH:33][C:32](Br)=[CH:31][N:30]=2)=[O:28])[CH2:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O>[N:23]1([C:27]([C:29]2[N:30]=[CH:31][C:32]([O:22][C:20]3[CH:19]=[C:9]([CH:8]=[C:7]([O:6][CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH:21]=3)[C:10]([NH:12][C:13]3[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=3)=[O:11])=[CH:33][CH:34]=2)=[O:28])[CH2:26][CH2:25][CH2:24]1
Reactant: Cn1ccc(NC(=O)c2cc(O)cc(OC3CCCC3)c2)n1
Reactant: O=C(c1ccc(Br)cn1)N1CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Cn1ccc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)nc3)cc(OC3CCCC3)c2)n1
Temperature: 200 °C

Procedure:
3-(Cyclopentyloxy)-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide (200 mg, 0.67 mmol), 2-(azetidin-1-ylcarbonyl)-5-bromopyridine (193 mg, 0.80 mmol), bromotris(triphenylphosphine)copper (186 mg, 0.2 mmol) and caesium carbonate (230 mg, 0.70 mmol) were dissolved/suspended in DMA (3.5 mL). The reaction mixture was heated for 40 mins at 200° C. in a microwave reactor then allowed to cool, filtered and reduced in vacuo. The crude product was purified by chromatography on silica, eluting with 0-100% ethyl acetate in isohexane, to give the desired compound as a slightly yellow foam (176 mg). 1H NMR δ (d6-DMSO): 1.61 (m, 2H), 1.73 (m, 4H), 1.94 (m, 2H), 2.28 (m, 2H), 3.78 (s, 3H), 4.08 (t, 2H), 4.59 (t, 2H), 4.95 (m, 1H), 6.56 (d, 1H), 6.88 (t, 1H), 7.28 (m, 1H), 7.43 (t, 1H), 7.56 (m, 1H), 7.59 (d, 1H), 7.99 (d, 1H), 8.41 (m, 1H), 10.85 (s, 1H); m/z 462 (M+H)+
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[CH:13]=[N:12]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:26][C:27]1[CH:31]=[CH:30][N:29]([CH2:32][C:33]([CH3:36])([OH:35])[CH3:34])[N:28]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[CH:13]=[N:12]2)[C:8]([NH:26][C:27]2[CH:31]=[CH:30][N:29]([CH2:32][C:33]([OH:35])([CH3:34])[CH3:36])[N:28]=2)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccccc1Oc1cnn(C(CC2CCCC2)C(=O)O)c(=O)c1
Reactant: CC(C)(O)Cn1ccc(N)n1
Product: Cc1ccccc1Oc1cnn(C(CC2CCCC2)C(=O)Nc2ccn(CC(C)(C)O)n2)c(=O)c1
Yield: 58 %

Procedure:
Using the method described in Example 17, 3-cyclopentyl-2-(6-oxo-4-o-tolyloxy-6H-pyridazin-1-yl)-propionic acid (Intermediate 41) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(6-oxo-4-o-tolyloxy-6H-pyridazin-1-yl)-propionamide as a white solid (0.86 g, 58%); ES+-HRMS m/e calcd for C26H33N5O4 [M+H+] 480.2606 found 480.2605. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.05 (s, 3H), 1.06 (s, 3H), 1.09 (m, 1H), 1.27-1.75 (m, 8H), 1.92 (m, 1H), 2.16 (s, 3H), 2.27 (m, 1H), 3.89 (s, 2H), 4.67 (s, 1H), 5.45 (dd, J=4.3, J=10.9 Hz, 1H), 5.56 (d, J=2.8 Hz, 1H), 6.40 (d, J=2.3 Hz, 1H), 7.21 (dd, Jo=7.5 Hz, Jm=1.3 Hz, 1H), 7.28 (td, Jo=7.5 Hz, Jm=1.3 Hz, 1H), 7.34 (td, Jo=7.5 Hz, Jm=1.3 Hz, 1H), 7.41 (d, Jo=7.5 Hz, 1H), 7.53 (d, J=2.3 Hz, 1H), 8.15 (d, J=2.8 Hz, 1H), 10.80 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C@@H:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15](=O)OCC3C=CC=CC=3)[CH2:9]2)[CH2:4][CH2:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>C1COCC1>[CH3:15][NH:14][C@H:10]1[CH2:11][CH2:12][CH2:13][C@@H:8]([N:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)[CH2:9]1
Reactant: CN1CCN([C@@H]2CCC[C@H](NC(=O)OCc3ccccc3)C2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN[C@H]1CCC[C@@H](N2CCN(C)CC2)C1
Yield: 94 %

Procedure:
Benzyl (1S,3R)-3-(4-methylpiperazin-1-yl)cyclohexylcarbamate (2.0 g, 6.0472 mmol, 1.0 eq.) was dissolved in THF (10 ml) and added dropwise at 0° C. to a suspension of LAH (0.345 g, 9.06 mmol, 1.5 eq.) in THF (30 ml). The reaction mixture was then refluxed for 30 minutes. The reaction mixture was subsequently cooled to 0° C., hydrolyzed with 10% NaOH solution (0.35 ml), filtered off and washed with THF (2×50 ml). The filtrate was concentrated under reduced pressure and dried. Yield: 94% (1.2 g, 5.68 mmol)
Reaction SMILES: I[C:2]1[C:6]2[C:7]([O:11][CH3:12])=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[Cl:32][C:33]1[CH:38]=[C:37](B(O)O)[CH:36]=[CH:35][N:34]=1.C(#N)C.C([O-])(=O)C.[K+]>O.ClCCl>[Cl:32][C:33]1[CH:38]=[C:37]([C:2]2[C:6]3[C:7]([O:11][CH3:12])=[N:8][CH:9]=[CH:10][C:5]=3[N:4]([C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:3]=2)[CH:36]=[CH:35][N:34]=1
Reactant: COc1nccc2c1c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OB(O)c1ccnc(Cl)c1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: COc1nccc2c1c(-c1ccnc(Cl)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 100 °C
Yield: 79.8 %

Procedure:
To a microwave vial was charged 3-iodo-4-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine (1.14 g, 2.21 mmol), 2-chloropyridin-4-ylboronic acid (0.366 g, 2.32 mmol) and bis(diphenylphosphino)ferrocenepalladium chloride (181 mg, 0.221 mmol). Acetonitrile (14 mL, 270 mmol) and 1.0 M of potassium acetate in water (5.3 mL) were then added and the reaction mixture was degassed with nitrogen for 10 minutes and then heated to 100° C. under microwave irradiation for 40 minutes. Upon reaction completion, the reaction mixture was diluted with dichloromethane, filtered through Celite® and concentrated in vacuo. The crude residue was purified by column chromatography eluting with 0-2% EtOAc in DCM to give the title compound (0.887 g, 80%). LC-MS (Method H): m/z=503.3 [M+H]+, 1.55 min. 1H-NMR (400 MHz, CDCl3): δ 8.38 (d, J=4.6, 1H), 8.06 (s, 1H), 7.86 (d, J=4.8, 1H), 7.58 (d, J=6.0, 1H), 7.35-7.28 (m, 9H), 7.23-7.14 (m, 6H), 5.91 (d, J=6.2, 1H), 4.11 (s, 3H.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][C@H:18]3[CH3:23])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.C=O.[BH3-][C:27]#N.[Na+].O>CO.C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH3:27])[CH2:19][C@H:18]3[CH3:23])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: [BH3-]C#N
Reactant: C[C@@H]1CNCCN1c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: C[C@@H]1CN(C)CCN1c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 92.7 %

Procedure:
A mixture of 115d (500 mg, 1.3 mmol) and 30% formaldehyde (650 mg, 6.5 mmol) in methanol/acetic acid (30 mL/3 mL) was stirred at room temperature for 5 minutes, followed by the addition of NaBH3CN (120 mg, 1.9 mmol). The mixture was stirred at room temperature for 4 h. water (20 mL) was added and the resulting mixture was concentrated under reduced pressure. The residue was extracted with dichloromethane (3×30 mL). The combined organic layer was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 115e as a yellow solid (473 mg, 92%). MS-ESI: [M+H]+ 392.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N+:10]([O-])=O)[C:6]([CH3:9])=[N:7][CH:8]=1)#[CH:2].[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>CCO.[OH-].[OH-].[Pd+2]>[CH3:9][C:6]1[C:5]([NH2:10])=[CH:4][C:3]([CH2:1][CH2:2][N:17]2[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]2)=[CH:8][N:7]=1
Reactant: CN1CCNCC1
Reactant: C#Cc1cnc(C)c([N+](=O)[O-])c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: Cc1ncc(CCN2CCN(C)CC2)cc1N
Temperature: 25 °C
Yield: 76.6 %

Procedure:
To a solution of 5-ethynyl-2-methyl-3-nitropyridine (600 mg, 3.70 mmol) in EtOH (10 mL) was added 1-methyl-piperazine (1.64 mL, 14.8 mmol). The reaction mixture was allowed to stir at reflux overnight. The reaction mixture was allowed to cool to rt and palladium hydroxide on carbon (0.060 g) was added to the solution. The reaction mixture was purged with hydrogen and then allowed to stir under an atmosphere of H2 at rt overnight. The reaction mixture was filtered through celite and the filatrate was concentrated. The residue was purified by column chromatography to give 2-methyl-5-[2-(4-methylpiperazin-1-yl)ethyl]pyridin-3-amine (0.664 g, 77%).
Reaction SMILES: [F:1][C@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.C(OC([NH:33][C:34]1[S:38][C:37]([C:39]2[CH:44]=[C:43]([Cl:45])[CH:42]=[CH:41][C:40]=2[F:46])=[N:36][C:35]=1[C:47](O)=[O:48])=O)(C)(C)C>>[NH2:33][C:34]1[S:38][C:37]([C:39]2[CH:44]=[C:43]([Cl:45])[CH:42]=[CH:41][C:40]=2[F:46])=[N:36][C:35]=1[C:47]([NH:23][C:18]1[CH:19]=[N:20][N:21]([CH3:22])[C:17]=1[C@@H:5]1[CH2:6][CH2:7][C@@H:8]([NH2:9])[C@H:2]([F:1])[CH2:3][O:4]1)=[O:48]
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2cc(Cl)ccc2F)nc1C(=O)O
Product: Cn1ncc(NC(=O)c2nc(-c3cc(Cl)ccc3F)sc2N)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 80), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 5-((tert-butoxycarbonyl)amino)-2-(5-chloro-2-fluorophenyl)thiazole-4-carboxylic acid (Intermediate 132) gave 291. 1H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.29 (dd, J=6.5, 2.7 Hz, 1H), 7.73 (bs, 1H), 7.51 (s, 2H), 7.48-7.36 (m, 2H), 7.08-6.53 (m, 1H), 4.85 (dd, J=9.9, 4.1 Hz, 1H), 4.51-4.31 (m, 1H), 4.29-3.93 (m, 2H), 3.78 (s, 3H), 2.18-2.07 (m, 1H), 1.93-1.79 (m, 1H), 1.78-1.62 (m, 3H). LCMS (ES+) m/z 483 (M+1).
Reaction SMILES: [CH3:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].C([N-]C(C)C)(C)C.[Li+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>O1CCCC1>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][CH:2]([CH3:1])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:4])[CH3:27]
Reactant: CCC(=O)c1ccc(OC)cc1
Reactant: CCOC(=O)CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(C)C(=O)c1ccc(OC)cc1
Temperature: 25 °C
Yield: 125.6 %

Procedure:
A solution of 4-methoxypropiophenone (24 g, 140 mmol) in tetrahydrofuran (220 mL) was cooled to 0° C. Lithium diisopropylamide, (2M solution in THF) (126 mL, 248 mmol) was added dropwise and warmed to rt for 30 min. The reaction was cooled again to 0° C. and ethyl bromoacetate (18 mL, 161 mmol) was added dropwise and warmed to rt for 30 min and then quenched with aqueous 1M HCl acid at 0° C. The aqueous layer was extracted twice with methylene chloride and the combined organics were washed with brine, dried (Na2SO4), filtered, and concentrated to give 4-(4-methoxyphenyl)-3-methyl-4-oxobutyric acid ethyl ester (44 g), MS m/z 205 (M-45).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][C:9](C)([CH3:41])[CH2:10][NH:11][CH2:12][C:13]1[O:17][CH:16]=[C:15]([C:18]2[CH:19]=[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=2)[NH:23][CH:22]=[C:21]3[CH:30]2[CH2:35][CH2:34][N:33]([S:36]([CH2:39][CH3:40])(=[O:38])=[O:37])[CH2:32][CH2:31]2)[CH:14]=1.CC(C)(C)CN>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:39]([S:36]([N:33]1[CH2:34][CH2:35][CH:30]([C:21]2[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=[C:18]([C:15]4[CH:14]=[C:13]([CH2:12][NH:11][CH2:10][CH:9]([CH3:41])[CH3:8])[O:17][CH:16]=4)[CH:19]=3)[NH:23][CH:22]=2)[CH2:31][CH2:32]1)(=[O:37])=[O:38])[CH3:40]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4coc(CNCC(C)(C)C)c4)cc23)CC1
Agent: CC(C)(C)CN
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4coc(CNCC(C)C)c4)cc23)CC1
Yield: 37.7 %

Procedure:
The title compound was prepared according to the general procedure of 5-(5-{[(2,2-dimethylpropyl)amino]methyl}-3-furanyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting 2-methyl-1-propanamine (102.4 mg, 1.4 mmol) for 2,2-dimethyl-1-propanamine to afford 31.7 mg of the title compound (37.7%).
Reaction SMILES: [CH:1]1([CH2:4][C:5]([F:9])([F:8])[CH2:6][OH:7])[CH2:3][CH2:2]1.C(N(CC)CC)C.[F:17][C:18]([F:33])([S:29](F)(=[O:31])=[O:30])[C:19]([F:28])([F:27])[C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22].[O-][Mn](=O)(=O)=O.[K+]>O.C(OCC)(=O)C.ClCCl>[F:33][C:18]([F:17])([S:29]([O:7][CH2:6][C:5]([F:9])([F:8])[CH2:4][CH:1]1[CH2:3][CH2:2]1)(=[O:31])=[O:30])[C:19]([F:27])([F:28])[C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22]
Reactant: OCC(F)(F)CC1CC1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=S(=O)(OCC(F)(F)CC1CC1)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 0 °C
Yield: 95.6 %

Procedure:
3-Cyclopropyl-2,2-difluoro-1-propanol (48.0 g 0.35 mol, 1 eq), prepared as in Example 4, was added to a 1 L jacketed vessel equipped with a mechanical stirrer, thermometer and gas inlet adapter. Dichloromethane (480 mL) and then triethylamine (42.7 g, 0.421 mol, 1.2 eq) was added. The reaction mixture was cooled to 0° C. and then perfluorobutane sulfonyl fluoride (127.9 g, 0.421 mol, 1 eq) was slowly added drop wise over 30 minutes maintaining a temperature of less than 5° C. The reaction was shown to be complete after one hour by thin layer chromatography (1:1/ethyl acetate:hexanes, silica, KMnO4 dip). The mixture was concentrated under vacuum at 30° C. to provide a brown oil. Water (150 mL) was added and the product was extracted with methyl tert-butylether (250 mL). The organic layer was washed with water (2×150 mL), dried with anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to provide 3-cyclopropyl-2,2-difluoropropyl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (140 g, 95% yield) as a brown oil. GC/MS: consistent with mass.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[O:7]1[CH:12]=[CH:11][CH2:10][CH2:9][CH2:8]1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[O:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[O:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1]
Reactant: OCCCCBr
Reactant: C1=COCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: BrCCCCOC1CCCCO1
Reaction time: 4 h
Yield: 96 %

Procedure:
16.0 g (105.0 mmols) of 4-bromobutanol was dissolved in 140 ml of chloroform, and a solution prepared by dissolving 13.9 ml (1.5-fold equivalent weight) of 3,4-dihydro-2H-pyran in 40 ml of chloroform was dropwise added thereto at 0° C. in an atmosphere of argon. The solution obtained was stirred for 4 hours while keeping it at 0° C., followed by addition of an aqueous sodium hydrogencarbonate, and the resulting solution was extracted with chloroform (100 ml×2). The organic layer obtained was dried with anhydrous sodium sulfate, and thereafter concentrated under reduced pressure to obtain 24.0 g of 4-(tetrahydropyran-2-yl)oxybutyl bromide (yield: 96%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]([O:13]CC)=[O:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C1COCC1.O.[OH-].[Li+].Cl>CO.O>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]([OH:13])=[O:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C1CCC2(CC1)OCCO2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 101 %

Procedure:
Ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate (79.58 mmol, 17.05 g) is taken up in 300 mL 2:1 THF:H2O in 500 mL roundbottom flask. Lithium hydroxide monohydrate (120 mmol, 5.01 g) and 100 mL MeOH were added to this solution. The reaction mixture was allowed to stir overnight at room temperature. The reaction mixture was acidified to pH 3 with 1N HCl(aq) and extracted with 100 mL DCM (×5). The combined organics were combined and then dried over Na2SO4, and the solvent was removed in vacuo to yield 1,4-dioxaspiro[4.5]decane-8-carboxylic acid (14.96 g, 100% yield) as white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[O-]CC.[Na+].[C:15](OCC)(=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17].[Na].C(C(C(=O)C1C=CC=CC=1N)C(=O)C(O)=O)C>C(O)C>[O:10]=[C:8]1[C:3]2[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=2)[NH:1][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:9]1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1ccccc1N
Agent: CCC(C(=O)C(=O)O)C(=O)c1ccccc1N
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc(=O)c2ccccc2[nH]1
Yield: 57.5 %

Procedure:
1.35 g (10 mMol) of 1-(2'-aminophenyl)ethanone was heated under reflux with 40 mMol of sodium ethoxide and 40 mMol of diethyl oxalate in 70 ml of ethanol for 21/2 hr. The reaction mixture, which contained the sodium salt of ethyl (2-aminobenzoyl)pyruvic acid was poured into ice/hydrochloric acid and extracted with chloroform. Concentration to dryness and boiling with diethyl ether gave 1.25 g (58%) of the title product, mp 210°-212°.