Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:25])[N:4]([CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[C:5]([CH3:17])=[CH:6][C:7]=1[C:8]#[C:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1.[H][H]>C(OCC)(=O)C.CCO.O=[Pt]=O>[Br:1][C:2]1[C:3](=[O:25])[N:4]([CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[C:5]([CH3:17])=[CH:6][C:7]=1[CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=1
Reactant: Cc1cc(C#Cc2ccc(F)cc2)c(Br)c(=O)n1Cc1cccnc1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(CCc2ccc(F)cc2)c(Br)c(=O)n1Cc1cccnc1
Yield: 23.3 %

Procedure:
A suspension of 3-bromo-4-[(4-fluorophenyl)ethynyl]-6-methyl-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one (0.430 g, 1.01 mmol) in Ethyl acetate (5 mL) and EtOH (5 mL), containing PtO2 (0.015 g) was stirred in an atmosphere of hydrogen (15 psi) in a Fischer-Porter bottle for 2 hours. The reaction mixture was filtered and the filtrate was concentrated to reduce volume. The material was purified by flash column chromatography (ethyl acetate). The appropriate fractions were combined and concentrated under reduced pressure to afford the desired product (0.0943 g, 22%) as a sticky semisolid after drying. 1H-NMR (CD3OD, 400 MHz) δ 8.46 (d, 2H, J=26.4 Hz), 7.60 (d, 1H, J=8.0 Hz), 7.41 (dd, 1H, J=4.8 Hz, 4.8 Hz), 7.21 (m, 2H), 6.97 (t, 2H, J=8.8 Hz), 6.24 (s, 1H), 5.43 (s, 2H), 2.93 (m, 4H), 2.31 (s, 3H); ES-HRMS m/z 401.0645/403.0603 (M+H calculated for C20H19N2OFBr requires 401.0659/403.0641).
Reaction SMILES: [Cl-:1].[Al+3].[Cl-].[Cl-].[CH:5]1[C:10](Cl)=[CH:9][CH:8]=[C:7]([Cl:12])[CH:6]=1.[C:13]([N:16]1[CH2:24][CH2:23][CH:19]([C:20](Cl)=[O:21])[CH2:18][CH2:17]1)(=[O:15])[CH3:14]>O>[Cl:1][C:9]1[CH:8]=[C:7]([Cl:12])[CH:6]=[CH:5][C:10]=1[C:20]([CH:19]1[CH2:18][CH2:17][N:16]([C:13](=[O:15])[CH3:14])[CH2:24][CH2:23]1)=[O:21]
Reactant: [Cl-]
Reactant: Clc1ccc(Cl)cc1
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Agent: [Al+3]
Solvent: O
Product: CC(=O)N1CCC(C(=O)c2ccc(Cl)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
Aluminium chloride (11, 24 g, 84 mmol) is added portionwise to 23 mL of dichlorobenzene (200 mmol). To this suspension 8 g of 1-acetylisonipecotoyl chloride (42 mmol) was added also portionwise. The mixture was stirred 10 minutes at room temperature and then at 90° C. for 4 hours until TLC indicated completion of the reaction that changed from a yellow/orange solution changed into dark orange upon heating. Water was added and the solution was extracted three times with dichloromethane. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by flash-chromatography on silica gel with hexane:ethyl acetate (1:0 to 0:1) to give 6.3 g (50%) of the product as an orange oil. MS (m/e): 300.2 (M+).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]2[C:9](=[CH:11][C:12]3[N:13]=[C:14]([NH:18][C:19](=[O:22])[CH2:20]Cl)[S:15][C:16]=3[CH:17]=2)[N:10]=1)=[O:4].[CH2:23]([NH:26][CH2:27][CH2:28][CH3:29])[CH2:24][CH3:25]>O1CCOCC1>[ClH:1].[ClH:1].[CH2:23]([N:26]([N:18]([C:19](=[O:22])[CH3:20])[C:14]1[S:15][C:16]2[C:12](=[CH:11][C:9]3[N:10]=[C:6]([N:5]([N:26]([CH2:27][CH2:28][CH3:29])[CH2:23][CH2:24][CH3:25])[C:3](=[O:4])[CH3:2])[S:7][C:8]=3[CH:17]=2)[N:13]=1)[CH2:27][CH2:28][CH3:29])[CH2:24][CH3:25]
Reactant: O=C(CCl)Nc1nc2cc3nc(NC(=O)CCl)sc3cc2s1
Reactant: CCCNCCC
Solvent: C1COCCO1
Product: CCCN(CCC)N(C(C)=O)c1nc2cc3nc(N(C(C)=O)N(CCC)CCC)sc3cc2s1
Product: Cl

Procedure:
A mixture of 7.2 gm of 2,6-bis-(chloroacetyl-amino)-benzo[1,2-d:5,4-d']bisthiazole, 10 gm of di-n-propylamine and 100 ml of dioxane was refluxed for two hours and then evaporated to dryness in vacuo. The residue was dissolved in chloroform, and the solution was washed with water, dried, evaporated to a small volume and chromatographed on a 300 gm silicagel column with chloroform and chloroform/methanol (95:5) as the mobile phase. The title compound, 2.5 gm (25.5% of theory), was eluted, dissolved in chloroform, treated with gaseous hydrogen chloride, and the collected hydrochloride was recrystallized from ethanol/water. M.P. 210° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:65][C:66]1[CH:67]=[C:68]([CH:71]=[CH:72][CH:73]=1)[C:69]#[N:70]>C(Cl)Cl>[C:69]([C:68]1[CH:67]=[C:66]([NH:65][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[NH:10]2)=[O:29])[CH:73]=[CH:72][CH:71]=1)#[N:70]
Reactant: N#Cc1cccc(N)c1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2cccc(C#N)c2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (250 mg, 0.54 mmol) in methylene chloride (10 mL), HATU (Aldrich, 247 mg, 0.65 mmol) was added followed by the addition of DIPEA (0.65 mmol) and 3-amino benzonitrile (Aldrich, 77 mg, 0.65 mmol). The mixture was stirred at rt overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, eluent, 35-50% EtOAc/hexanes) to give a white solid. 84 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[C:11]([CH:15]=1)[C:12](O)=[O:13].[CH2:32]([CH:34]([NH2:37])[CH2:35][CH3:36])[CH3:33].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)=[C:11]([CH:15]=1)[C:12]([NH:37][CH:34]([CH2:35][CH3:36])[CH2:32][CH3:33])=[O:13]
Reactant: COc1c(C)c(Cc2ccc(-c3ccncc3)c(C(=O)O)c2)c(OC)c(OC)c1OC
Reactant: CCC(N)CC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCC(CC)NC(=O)c1cc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)ccc1-c1ccncc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 54.1 %

Procedure:
5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(4-pyridyl)benzoic acid (100 mg, 0.2364 mmol) and 1-ethylpropylamine (66 mg, 0.7586 mmol) were dissolved in methylene chloride (5 ml), then 4-dimethylaminopyridine (6 mg, 0.0491 mmol) and WSC-HCl (146 mg, 0.7616 mmol) were added thereto and the mixture was stirred for 6 hours at room temperature. The reaction solution was washed with water and dried and the solvent was evaporated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:5) to give N-[5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-(4-pyridyl)benzoyl]-1-ethylpropylamine (63 mg, 0.1280 mmol, 54%).
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]#[N:33])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Sn]([N:47]=[N+:48]=[N-:49])(CCCC)CCCC)CCC>C(OCC)(=O)C>[C:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]3[N:47]=[N:48][NH:49][N:33]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CCCCCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: CCOC(C)=O
Product: c1ccc(-c2nn(CCCCCCCCc3nn[nH]n3)c(-c3ccccc3)c2-c2ccccc2)cc1
Temperature: 140 °C
Reaction time: 2.5 h
Yield: 72.3 %

Procedure:
A mixture of 3,4,5-triphenyl-lH-pyrazole-1-nonanenitrile (1.25 g, 2.9 mmol) and tri-n-butyltin azide (1.15 g, 3.5 mmol) was heated with stirring at 140° C. under an atmosphere of nitrogen. After 2.5 hours, the mixture was cooled to room temperature, diluted with ethyl acetate and washed with 0.5 N HCl (3 x) and saturated sodium chloride solution before being dried and concentrated in vacuo. The residual oil was chromatographed on a column of silica gel using first a mixture of ethyl acetate and hexane (1:1) and subsequently methanol/chloroform (1:9) as eluent. The recovered oil was dissolved in CH2Cl2 and stirred with a concentrated aqueous solution of potassium floride. After 24 hours, the layers were separated and the aqueous layer extracted with dichloromethane. The organic extracts were dried over sodium sulfate and concentrated in vacuo to give an oil that solidified. Recrystallization from a mixture of hexane and dichloromethane (2:1) afforded the title compound (1.00 g, 73%); m.p.=158°-160° C. MS(CI): m/e =477 (MH+).
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]([NH2:17])=[O:16])=[N:8][C:7]=3[C:6]=2[CH:18]=1.[CH3:20][C:21]([OH:25])([C:23]#[CH:24])[CH3:22]>CS(C)=O.C(N(CC)CC)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:19][C:3]1[C:2]([C:24]#[C:23][C:21]([OH:25])([CH3:22])[CH3:20])=[CH:18][C:6]2[C:7]3[N:8]=[C:9]([C:15]([NH2:17])=[O:16])[S:10][C:11]=3[CH2:12][CH2:13][O:14][C:5]=2[CH:4]=1
Reactant: NC(=O)c1nc2c(s1)CCOc1cc(F)c(Br)cc1-2
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(O)C#Cc1cc2c(cc1F)OCCc1sc(C(N)=O)nc1-2

Procedure:
The title compound was prepared according to a procedure similar to that described in Procedure G. Into a 8-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed a suspension of 9-Bromo-8-fluoro-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide (300 mg, 0.87 mmol, 1.00 equiv), 2-methylbut-3-yn-2-ol (260 mg, 3.09 mmol, 3.50 equiv) and Pd(PPh3)2Cl2 (60 mg, 0.09 mmol, 0.10 equiv) in DMSO (1 mL) and triethylamine (1 mL). The final reaction mixture was irradiated with microwave radiation for 1 h at 70° C. The resulting solution was diluted with 20 mL of water. The solids were collected by filtration and washed with 20 mL of ethyl acetate. This resulted in 0.24 g (79%) of 8-Fluoro-9-(3-hydroxy-3-methyl-but-1-ynyl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide as a off-white solid. LC-MS (ES, m/z): 347[M+H]+; 1H-NMR: (300 MHz, DMSO-d6, ppm) δ 8.652 (d, 1H), 8.460 (s, 1H), 7.860 (s, 1H), 7.007 (d, 1H), 5.497 (s, 1H), 4.391 (t, 2H), 3.414 (t, 2H), 1.491 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1.[C:17]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)(=O)[CH3:18].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][CH:17]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH3:18])=[CH:9][CH:10]=1
Reactant: Nc1ccc(Oc2ccc(F)cc2F)cc1
Reactant: CC(=O)c1cccnc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(Nc1ccc(Oc2ccc(F)cc2F)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A solution of N-(4-(2,4-difluorophenoxy)phenyl)amine (1.0 equiv.) in dichloromethane (0.2 M) was cooled to 0° C. and treated with 3-acetylpyridine (Aldrich; 1.4 equiv.), acetic acid (5.0 equiv.), and sodium triacetoxyborohydride (2.5 equiv.). The reaction was allowed to warm to ambient temperature and stirred an additional 22 hours. The reaction was cautiously quenched with saturated aqueous NaHCO3 then adjusted to pH=10 with 1 N NaOH. The mixture was stirred for 4 hours then the layers were separated. The aqueous layer was extracted twice with DCM. The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude material was purified via radial chromatography eluting with 50:50 to 60:40 ethyl acetate/hexanes to give N-(4-(2,4-difluorophenoxy)phenyl)-1-pyrid-3-ylethylamine. 1H NMR (400 MHz) 1.54 (3H, d, J=6.7 Hz), 3.96 (1H, bs), 4.48 (1H, q, J=6.7 Hz), 6.44 (2H, m), 6.76 (2H, m), 6.83-6.93 (2H, m), 7.24 (1H, m), 7.44 (1H, m), 7.68 (1H, td, J=1.8, 7.9 Hz), 8.50 (1H, d, J=3.8 Hz), 8.64 (1H, bs). HRMS calcd 327.1309. Found 327.1308.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:12][C@H:5]2[CH2:6][N:7]([C:9]([NH2:11])=[O:10])[CH2:8][C@@:4]2([C:13]([N:15]2[CH2:24][CH2:23][C:22]3[C:17](=[CH:18][C:19]([C:25]([F:28])([F:27])[F:26])=[CH:20][CH:21]=3)[CH2:16]2)=[O:14])[CH2:3]1.[CH3:29][O:30][CH:31]1[C:36](=O)[CH2:35][CH2:34][O:33][CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:29][O:30][C@H:31]1[C@@H:36]([NH:1][C@@H:2]2[CH2:12][C@H:5]3[CH2:6][N:7]([C:9]([NH2:11])=[O:10])[CH2:8][C@@:4]3([C:13]([N:15]3[CH2:24][CH2:23][C:22]4[C:17](=[CH:18][C:19]([C:25]([F:28])([F:27])[F:26])=[CH:20][CH:21]=4)[CH2:16]3)=[O:14])[CH2:3]2)[CH2:35][CH2:34][O:33][CH2:32]1
Reactant: COC1COCCC1=O
Reactant: NC(=O)N1C[C@@H]2C[C@@H](N)C[C@]2(C(=O)N2CCc3ccc(C(F)(F)F)cc3C2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CO[C@@H]1COCC[C@@H]1N[C@@H]1C[C@H]2CN(C(N)=O)C[C@@]2(C(=O)N2CCc3ccc(C(F)(F)F)cc3C2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the product from Step B (316 mg, 0.62 mmol), 3-methoxydihydro-2H-pyran-4(3H)-one (242 mg, 1.86 mmol), 4 Å molecular sieves (0.3 g) and TEA (0.259 mL, 1.86 mmol) in DCM (8 mL) was stirred at rt for 2 h, followed by addition of sodium triacetoxyborohydride (263 mg, 1.24 mmol). The resulting mixture was stirred at rt overnight. The reaction was quenched by the addition of saturated NaHCO3 aqueous solution, extracted with DCM, and dried over Na2SO4. After removal of the solvent, the residue was purified by column chromatography (eluent: EtOAc to 15% 7N NH3 in methanol in EtOAc) to give the product as a white foam. 1H-NMR (400 MHz, CDCl3): δ 1.76 (br. s., 1H), 1.89-2.41 (m, 4H), 2.53 (br. s., 1H), 2.85-2.99 (m, 2H), 3.06-4.02 (m, 18H), 4.12 (q, J=7.1 Hz, 1H), 4.69 (br. s., 2H), 5.17-5.31 (m, 1H), 7.25 (d, J=7.8 Hz, 1H), 7.34-7.49 (m, 2H); LC/MS: C25H33F3N4O4: m/z 511.0 (M+H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]#[N:15].O.[OH-].[Li+]>CS(C)=O>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]#[N:15])([O-:10])=[O:9]
Reactant: N#Cc1ccccc1N
Reactant: O=[N+]([O-])c1ccccc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccccc1Nc1ccccc1[N+](=O)[O-]
Temperature: 55 °C
Reaction time: 19 h
Yield: 72.4 %

Procedure:
Combine 1-fluoro-2-nitro-benzene (5.00 g, 35.44 mmol), 2-amino-benzonitrile (4.19 g, 35.44 mmol), lithium hydroxide monohydrate (2.97 g, 70.87 mmol) and DMSO (50.0 ml). Stir the mixture at 55 ° C. for 19 hours then cool to ambient temperature. Pour the mixture onto ice chips and stir for 1 hour. Remove the resulting precipitate by vacuum filtration. Dry the precipitate under vacuum to give 6.14 g (72%) of an orange solid: mp 134–138°.
Reaction SMILES: NC[CH2:3][CH:4]([OH:6])[CH3:5].[CH2:7]([N:9](CC)CC)C.Br[CH2:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>CN(C=O)C>[C:20]([O:19][C:17](=[O:18])[CH2:16][CH2:15][NH:9][CH2:7][C:4]([OH:6])([CH3:3])[CH3:5])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)CCBr
Reactant: CC(O)CCN
Reactant: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(O)CNCCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 82 %

Procedure:
1 g of 1-aminomethylpropan-2-ol (11.22 mmol) is placed in 10 ml of DMF. 1.58 ml of triethylamine (11.22 mmol) and 1.87 ml of tert-butyl 3-bromopropionate (11.22 mmol) prediluted in 5 ml of DMF are successively added dropwise. After stirring for 18 hours at room temperature, the solvent is evaporated off. The residue is chromatographed on silica gel with a gradient of from 0% to 20% MeOH in DCM to give 2 g of 3-(2-hydroxy-2-methylpropylamino)propionic acid tert-butyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]2=[O:14])([O-:3])=[O:2].[CH3:15][C:16]([CH3:21])([CH2:19]O)[CH2:17][OH:18].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1CCCCC1>[CH3:15][C:16]1([CH3:21])[CH2:17][O:18][C:7]2([C:6]3[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[NH:9][C:8]2=[O:13])[O:14][CH2:19]1
Reactant: CC(C)(CO)CO
Reactant: O=C1Nc2ccc([N+](=O)[O-])cc2C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCCCC1
Product: CC1(C)COC2(OC1)C(=O)Nc1ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Yield: 108.9 %

Procedure:
A mixture of 5-nitroindoline-2,3-dione (305 mg, 1.587 mmol), 2,2-dimethylpropane-1,3-diol (165 mg, 1.587 mmol) and p-toluenesulfonic acid monohydrate (catalytic amount) in cyclohexane (9 ml) was stirred at reflux temperature (removing water by a Dean-Stark apparatus) for 6 hours. The reaction was cooled to room temperature and the solid was recovered by filtration and washed with petroleum ether, affording 5,5-dimethyl-5′-nitrospiro[[1,3]dioxane-2,3′-indolin]-2′-one (481 mg). that was used as such in the following step. MS/ESI+ 279.0 [MH]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2([C:15](=[O:16])[NH:14][CH2:13][CH2:12]2)[CH:10]([OH:19])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([O-:23])([O-])=[O:21].[K+].[K+].[CH3:26][C:27]1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)O[C:29]2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=C[C:28]1=2.O>CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2([C:15](=[O:16])[N:14]([C:27]3[CH2:26][O:23][C:20](=[O:21])[C:28]=3[CH3:29])[CH2:13][CH2:12]2)[CH:10]([OH:19])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1NCCC12CCN(Cc1ccccc1)CC2O
Reactant: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC1=C(N2CCC3(CCN(Cc4ccccc4)CC3O)C2=O)COC1=O
Temperature: 60 °C

Procedure:
To a flask charged with 8-benzyl-6-hydroxy-2,8-diazaspiro[4.5]decan-1-one (520 mg, 2.0 mmol) and a stir bar was added palladium acetate (22 mg, 0.10 mmol), K2CO3 (550 mg, 4.00 mmol), Xantphos (120 mg, 0.20 mmol), 4-methyl-5-oxo-2,5-dihydrofuran-3-yltrifluoromethanesulfonate (640 mg, 2.6 mmol), and water (110 mg, 6.0 mmol). The mixture was heated to 60° C. for 2 hours. LC showed complete reaction at that point. The reaction was diluted with EtOAc, washed with water, and the phases separated. The crude solution was dried over Na2SO4, filtered and concentrated to an oil. The oil was loaded onto a silica gel column, and purified by MPLC with Hexane and EtOAc. Two spots were separated with the desired molecular weight in a ratio of about 1 to 7. The more polar spot was the major product. LCMS: m/z 357 (M+H)+.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:11][C:12]([NH:14][C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[CH:17][C:16]=1[F:24])=[O:13])([CH3:10])([CH3:9])[CH3:8].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>C1COCC1>[CH2:30]([O:29][C:27](=[O:28])[CH2:26][N:14]([C:12]([O:11][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:13])[C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[CH:17][C:16]=1[F:24])[CH3:31]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)Nc1c(F)cccc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CN(C(=O)OC(C)(C)C)c1c(F)cccc1[N+](=O)[O-]
Reaction time: 0.33 h

Procedure:
Potassium tert-butoxide (1 M in THF, 8,67 ml) is added (dropwise over 5 min) to a solution of N-(tert-butyloxycarbonyl)-2-fluoro-6-nitroaniline (XIX, EXAMPLE 21, 1.85 g) in THF (15 ml) cooled at 0°. After 20 min, ethyl bromoacetate (0.96 ml) is added dropwise over several minutes. The ice bath is removed and the reaction is stirred for 2 h, after which it is partitioned between ethyl acetate, aqueous sodium bicarbonate and saline. The phases are separated, the organic phase is dried over magnesium sulfate and concentrated to give the title compound, NMR (CDCl3) 1.26, 1.35, 1.50, 3.98, 4.10, 4.20, 4.42, 4.45, 7.42 and 7.39 δ.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]([C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1[F:23])(C(OC)=O)C(OC)=O)#[N:2].[Cl-].[Na+].O>CS(C)=O>[F:23][C:15]1[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:14]=1[CH2:5][CH2:4][CH2:3][C:1]#[N:2]
Reactant: COC(=O)C(CCC#N)(C(=O)OC)c1ccc([N+](=O)[O-])cc1F
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCCCc1ccc([N+](=O)[O-])cc1F
Temperature: 21 °C
Yield: 64.3 %

Procedure:
A solution of compound Dimethyl 2-(2-cyanoethyl)-2-(2-fluoro-4-nitrophenyl)malonate (73) (0.19 g, 0.59 mmol), sodium chloride (0.10 g, 1.76 mmol) and water (0.15 mL) in distilled dimethylsulfoxide (DMSO, 4 mL) was heated to 155° C. overnight. The reaction mixture was allowed to cool to 21° C. and then worked up by adding water and extracting with ethyl acetate (2×50 mL). The organic layer was dried over MgSO4, concentrated and the residue was purified with silica gel column chromatography (hexane:ethyl acetate, 8:1) to give desired 4-(2-Fluoro-4-nitrophenyl)butanenitrile (72) (79 mg, 65%): 1H NMR δ 8.02 (dd, 1H, J=8.3, 2.2 Hz), 7.94 (dd, 1H, J=9.5, 2.2 Hz), 7.42 (dd, 1H, J=8.3, 7.4 Hz), 2.93 (t, 2H, J=7.7 Hz) 2.41 (t, 2H, J=7.0 Hz) 2.01-2.07 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[CH2:5][CH:4]([C:6]([OH:8])=O)[CH2:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.O[N:22]=[C:23]([NH2:34])[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([N+:31]([O-:33])=[O:32])[CH:25]=1>CN1CCCC1=O.C(OCC)(=O)C.O>[CH3:30][C:27]1[CH:28]=[CH:29][C:24]([C:23]2[N:22]=[C:6]([CH:4]3[CH2:3][C:2](=[O:1])[CH2:5]3)[O:8][N:34]=2)=[CH:25][C:26]=1[N+:31]([O-:33])=[O:32]
Reactant: O=C1CC(C(=O)O)C1
Reactant: Cc1ccc(C(N)=NO)cc1[N+](=O)[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2noc(C3CC(=O)C3)n2)cc1[N+](=O)[O-]
Temperature: 130 °C
Reaction time: 0.08 h

Procedure:
To a stirring solution of 3-oxocyclobutanecarboxylic acid (595 mg, 5.12 mmol) in 1-methyl-2-pyrrolidinone (6 mL) was added 1,1′-carbonyldiimidazole (831 mg, 5.12 mmol). The reaction was stirred for 5 minutes. Then, N′-hydroxy-4-methyl-3-nitrobenzimidamide (27) (500 mg, 2.56 mmol) was added and the reaction was stirred for 15 minutes. Next, the reaction was heated in the microwave at 130° C. for 10 minutes. The crude product was taken in ethyl acetate and water. The organic was washed with 2× water/brine mixture and dried over anhydrous sodium sulfate. The solvent was concentrated and the crude product was purified by silica chromatography to afford 3-(3-(4-methyl-3-nitrophenyl)-1,2,4-oxadiazol-5-yl)cyclobutanone (122). MS m/z 274.07 (M+1)+.