Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:4]([OH:20])[C:5]2([C:18]#[N:19])[CH2:10][CH2:9][CH:8]([S:11]([CH2:14][CH:15]3[CH2:17][CH2:16]3)(=[O:13])=[O:12])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.O>N.CO.[Ni].CCO>[NH2:19][CH2:18][C:5]1([CH:4]([CH:1]2[CH2:2][CH2:3]2)[OH:20])[CH2:10][CH2:9][CH:8]([S:11]([CH2:14][CH:15]2[CH2:17][CH2:16]2)(=[O:12])=[O:13])[CH2:7][CH2:6]1
Reactant: N#CC1(C(O)C2CC2)CCC(S(=O)(=O)CC2CC2)CC1
Agent: [Ni]
Agent: N
Solvent: O
Solvent: CO
Solvent: CCO
Product: NCC1(C(O)C2CC2)CCC(S(=O)(=O)CC2CC2)CC1
Reaction time: 40 h

Procedure:
To 1-(cyclopropyl-hydroxy-methyl)-4-cyclopropylmethanesulfonyl-cyclohexanecarbonitrile (1.90 g; 6.39 mmol) in 2 M ammonia in methanol solution (20 ml) (nitrile did not dissolve) under a nitrogen atmosphere was added Raney Nickel (approx. 1 ml of 50% aqueous slurry). The resulting mixture was agitated under an atmosphere of hydrogen (50 psi) on a Parr apparatus for 40 hours. MS indicated that very little reduction of the nitrile had taken place. The mixture was filtered through a catalyst filter and the catalyst washed extensively with MeOH (300 ml, added in portions). The filtrate was evaporated in vacuo to give a greeny-white solid, which was transferred to the Parr flask as a suspension in EtOH (20 ml). Aqueous ammonia solution (1.5 ml) was added followed by Raney Nickel (approx. 1 ml of 50% aqueous slurry). The resulting mixture was agitated under an atmosphere of hydrogen (50 psi) on a Parr apparatus for 24 hours. MS indicated the presence of starting material (m/z=320, [M+Na]+), a small amount of product (m/z=302) and product with water eliminated (m/z=284). The mixture was filtered and the catalyst washed as before. The filtrate was evaporated in vacuo to give a greeny-white solid, which was triturated with MeOH and collected by filtration as a white solid (775 mg). NMR indicated that this was recovered starting material. The trituration filtrate was evaporated in vacuo and the residue was loaded in MeOH on to a SCX cartridge. The cartridge was washed with several column lengths of MeOH followed by 2M ammonia in methanol solution to elute the amine. The desired product was obtained as a green oil upon evaporation of the appropriate fractions (229 mg). m/z=302 (M+H+).
Reaction SMILES: Br[CH2:2]Br.[CH3:4][C:5]1[CH:11]=[CH:10][CH:9]=[C:7]([OH:8])[C:6]=1[OH:12]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-]>[CH3:4][C:5]1[C:6]2[O:12][CH2:2][O:8][C:7]=2[CH:9]=[CH:10][CH:11]=1
Reactant: BrCBr
Reactant: Cc1cccc(O)c1O
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Product: Cc1cccc2c1OCO2

Procedure:
11.6 g Adogen 464 and 7 mL of dibromomethane were refluxed in 50 mL of H20 for 0.5 hours under argon. 3-Methylcatechol (8.89 g, 71.6 mmol) was added over 2 hours and the mixture refluxed for an additional 1 hour. Distillation of the product from the reaction mixture afforded the title compound as a yellow oil: HRMS m/e 136.0524 (calc'd for C8H8O2, 136.0524).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][S:5][CH2:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[CH3:12].[S-:13][C:14]#[N:15].[K+]>C(O)C>[CH3:12][C:11]1[NH:10][CH:9]=[N:8][C:7]=1[CH2:6][S:5][CH2:4][CH2:3][S:13][C:14]#[N:15]
Reactant: Cc1[nH]cnc1CSCCCl
Reactant: N#C[S-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: Cc1[nH]cnc1CSCCSC#N

Procedure:
1-Chloro-2-(5-methyl-4-imidazolylmethylthio)ethane hydrochloride (2.1 g) and potassium thiocyanate (0.97 g) were heated together under reflux in ethanol (50 ml) for 3 days. The mixture was evaporated to dryness and the residue was taken up in water, basified with sodium carbonate and extracted with chloroform. The chloroform extracts were dried (MgSO4) and evaporated to a residue which was recrystallised from acetonitrile to give 2-(5-methyl-4-imidazolylmethylthio)ethylthiocyanate m.p. 101°-103°.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][CH:10]=[C:9]1[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([O:29][CH:30]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:31]([O:33]C)=[O:32])[CH:23]=[CH:22]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O>[CH2:1]([N:8]1[C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:11][CH:10]=[C:9]1[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([O:29][CH:30]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:31]([OH:33])=[O:32])[CH:23]=[CH:22]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(Cc1ccccc1)Oc1ccc2cc(-c3ccc(-c4ccccc4)n3Cc3ccccc3)ccc2c1
Solvent: O
Product: O=C(O)C(Cc1ccccc1)Oc1ccc2cc(-c3ccc(-c4ccccc4)n3Cc3ccccc3)ccc2c1
Yield: 89.8 %

Procedure:
In a similar manner as described in step 7 of Example 1, the title compound was prepared from methyl 2-{[6-(1-benzyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}-3-phenylpropanoate (0.145 g, 0.270 mmol), prepared in the previous step, and the addition of water (3 mL) to the reaction mixture. After the volatiles were removed under reduced pressure, the residue was partitioned between water and methylene chloride. The layers were separated and the aqueous layer was extracted one time with methylene chloride. The combined extracts were dried (MgSO4), filtered and the solvent removed under reduced pressure to give the title compound as an off-white solid (0.127 g, 90%), mp 70–80° C. Elemental Analysis for C36H29NO3.0.48 H2O Calc'd: C, 81.23; H, 5.67; N, 2.63. Found: C, 80.67; H 6.28; N, 2.36.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([CH3:23])=[C:6]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([C:21]#[N:22])[CH:16]=2)[C:7]([O:13][CH3:14])=[C:8]([CH:10](Cl)[CH3:11])[CH:9]=1.[CH3:24][C:25]1[C:33]2[C:28](=[N:29][CH:30]=[N:31][C:32]=2[NH2:34])[NH:27][N:26]=1.O>CN(C)C=O>[NH2:34][C:32]1[N:31]=[CH:30][N:29]=[C:28]2[N:27]([CH:10]([C:8]3[C:7]([O:13][CH3:14])=[C:6]([C:15]4[CH:20]=[CH:19][N:18]=[C:17]([C:21]#[N:22])[CH:16]=4)[C:5]([CH3:23])=[C:4]([Cl:3])[CH:9]=3)[CH3:11])[N:26]=[C:25]([CH3:24])[C:33]=12
Reactant: Cc1n[nH]c2ncnc(N)c12
Reactant: COc1c(C(C)Cl)cc(Cl)c(C)c1-c1ccnc(C#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1-c1ccnc(C#N)c1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
Sodium hydride (20 mg, 0.50 mmol) was added to a mixture of 4-[3-chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]pyridine-2-carbonitrile (90 mg, 0.28 mmol), 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (63 mg, 0.42 mmol) in N,N-dimethylformamide (4 mL) and the reaction was stirred et 30° C. overnight. The mixture was cooled, treated with water and then filtered to provide the desired product. LCMS calculated for C22H21ClN7O (M+H)+: m/z=434.1; Found: 434.2
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]1[CH:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([O:20][C:21](=[O:23])[CH3:22])[C@H:8](OC(=O)C)[O:7]1)(=[O:3])[CH3:2].[Br:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH:36]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][C:43]=3[CH3:45])[NH:38][CH2:37]2)=[CH:31][CH:30]=1.C(O)(=O)C>CO>[C:1]([O:4][CH2:5][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([O:20][C:21](=[O:23])[CH3:22])[C@H:8]([N:38]2[C:39]3[C:44](=[C:43]([CH3:45])[CH:42]=[CH:41][CH:40]=3)[CH:36]([CH2:35][C:32]3[CH:31]=[CH:30][C:29]([Br:28])=[CH:34][CH:33]=3)[CH2:37]2)[O:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)C1OC(C)=O
Reactant: Cc1cccc2c1C(Cc1ccc(Br)cc1)CN2
Solvent: CC(=O)O
Solvent: CO
Product: CC(=O)OC[C@H]1O[C@@H](N2CC(Cc3ccc(Br)cc3)c3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
Add [(2R,4S,5R,6S)-3,4,5,6-tetraacetoxytetrahydropyran-2-yl]methyl acetate (10.6 mmol) and 3-[(4-bromophenyl)methyl]-4-methyl-indoline (10.6 mmol) to a solution of acetic acid (69.8 mmol) in methanol (80 mL). Stir at room temperature overnight. Filter the reaction mixture through a glass frit and wash the filter cake with methanol (2×10 mL). Dry the filter cake under vacuum to yield the title compound (2.3g, 3.6 mmol): MS (m/z): 632 (M+H).
Reaction SMILES: C(O)C(O)C[O:4][CH2:5][CH:6]([OH:9])[CH2:7][OH:8].[C:12]([OH:41])(=[O:40])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].[Sn]>>[C:12]([OH:41])(=[O:40])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].[OH:4][CH2:5][CH:6]([CH2:7][OH:8])[OH:9].[OH:4][CH2:5][CH:6]([CH2:7][OH:8])[OH:9]
Reactant: OCC(O)COCC(O)CO
Agent: CCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: [Sn]
Product: OCC(O)CO
Temperature: 100 °C

Procedure:
112 g diglycerol (0.67 mole), 400 g montanic acid (1.0 mole) and 0.4 g tin powder were heated to 200° C. as in Example 1 with application of a gentle vacuum. The vacuum was increased to 24 mbar over a period of 3.4 h. The product had an acid value of approximately 1. A brown colored hard wax having a dropping point of 81° C. was obtained after cooling to 100° C., bleaching and filtering.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=3[C:13]=2[CH3:22])(=[O:11])=[O:10])=[C:4]([C:23]([F:26])([F:25])[F:24])[CH:3]=1.[CH3:27][O:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][N:30]=1>COCCOC.C(O)C.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>[CH3:27][O:28][C:29]1[N:34]=[CH:33][C:32]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]3[S:16][C:15]4[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=4[C:13]=3[CH3:22])(=[O:11])=[O:10])=[C:4]([C:23]([F:26])([F:24])[F:25])[CH:3]=2)=[CH:31][N:30]=1
Reactant: Cc1c(S(=O)(=O)Nc2ccc(Br)cc2C(F)(F)F)sc2ccc(F)cc12
Reactant: COc1ncc(B(O)O)cn1
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
Solvent: CCO
Product: COc1ncc(-c2ccc(NS(=O)(=O)c3sc4ccc(F)cc4c3C)c(C(F)(F)F)c2)cn1
Yield: 60.2 %

Procedure:
This compound was prepared in analogy to Example 2 starting from 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic acid(4-bromo-2-trifluoromethyl-phenyl)-amide (0.10 g) and 2-methoxy-5-pyrimidineboronic acid (0.066 g) in 1,2-dimethoxyethane (1.5 ml), ethanol (0.32 ml) and 2 M aqueous sodium carbonate solution (1.0 ml) with tetrakis(triphenylphosphine)palladium (0.012 g) to obtain the title compound (0.064 g) as a colorless solid. MS (ISP): 498.4 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([CH2:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18](Br)[CH:19]=3)[O:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:44]([O:48][CH3:49])(=[O:47])[CH:45]=[CH2:46]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:49][O:48][C:44](=[O:47])/[CH:45]=[CH:46]/[C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[O:14][C:11]1([CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]1)[CH2:22][C:21]2=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(Br)ccc1O2
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Temperature: 100 °C
Yield: 56.5 %

Procedure:
A mixture of 6-bromo-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylic acid tert-butyl ester (1.04 g, 2.62 mmol), Pd(OAc)2 (59 mg, 0.262 mmol), PPh3 (137 mg, 0.52 mmol), TEA (0.73 ml, 5.2 mmol), methyl acrylate (0.47 ml, 5.2 mmol) in dry DMF (10 ml) was heated at 100° C. for 8 h. The mixture was cooled down to RT, filtered on a celite pad and washed with AcOEt (100 ml). The filtrate was washed with NH4Cl and saturated NaHCO3 solution and brine. The organic phase was dried over Na2SO4 and evaporated under vacuum. The crude residue was purified by column chromatography (eluent:hexane/AcOEt 90:10 to 70:30) to give (E)-3-{1′-tert-butoxycarbonyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (594 mg) as a light yellow solid.
Reaction SMILES: [CH2:1]([NH2:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>O1CCCC1>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][NH:7][CH2:1][C:2]1[O:6][CH:5]=[CH:4][CH:3]=1)[CH3:21]
Reactant: NCc1ccco1
Reactant: CCOC(=O)CCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CNCc1ccco1
Temperature: 25 °C

Procedure:
Furfurylamine (48.6 g, 0.5 mol) and triethylamine (50.6 g, 0.5 mol) were dissolved in tetrahydrofuran (1000 mL) and cooled to 0°-5° C. with an ice water bath. Ethyl chloroacetate (61.3 g, 0.5 mol) was dropwise added at 0°-5° C. to the solution. After addition the mixture was allowed to warm up to room temperature and then stirred over night. The precipitated white triethylamine hydrochloride was filtered off and the filtrate concentrated to an oil which was dissolved in ether and cooled by means of an ice water bath. Ether which has been saturated with dry hydrogen chloride was added to the solution whereby the HCl salt of the product precipitated first as a sticky semisolid. Repeated treatment with anhydrous ether afforded the desired product. Filtration yielded 48.4 g product as an amber solid. Used as is for further synthesis.
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:13]=[C:9]([C:10](O)=[O:11])[C:8]([C:14](O)=[O:15])=[CH:7][C:6]=1[N+:17]([O-:19])=[O:18]>O1CCCC1>[F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:13]=[C:9]([CH2:10][OH:11])[C:8]([CH2:14][OH:15])=[CH:7][C:6]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc(Oc2ccc(F)cc2F)c([N+](=O)[O-])cc1C(=O)O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(CO)c(CO)cc1Oc1ccc(F)cc1F
Yield: 68.1 %

Procedure:
3.36 g of 5-(2,4-difluorophenoxy)-4-nitrophthalic acid in 20 ml of absolute tetrahydrofuran is reduced as described in Example 7(d) with 150 ml of a 0.3-molar borane-tetrahydrofuran complex solution in tetrahydrofuran. After crystallization from ethanol/water and ethyl acetate/hexane, 2.1 g of 5-(2,4-difluorophenoxy)-4-nitrophthalyl alcohol is obtained, mp 123.5°-124.5° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:20]=1)[C:8]([N:10]=[S@@:11]([CH3:19])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])#[CH:2].[CH3:21][C:22]([C:24]1[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=1)=[O:23]>>[C:22]([C:24]1[CH:29]=[CH:28][C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][CH:6]=[C:7]([CH:20]=2)[C:8]([N:10]=[S@@:11]([CH3:19])(=[O:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9])=[CH:26][CH:25]=1)(=[O:23])[CH3:21]
Reactant: C#Cc1cncc(C(=O)N=[S@@](C)(=O)c2ccccc2)c1
Reactant: CC(=O)c1ccc(I)cc1
Product: CC(=O)c1ccc(C#Cc2cncc(C(=O)N=[S@@](C)(=O)c3ccccc3)c2)cc1
Yield: 86 %

Procedure:
In a manner similar to that describe in Example 434 a mixture of (S)-5-ethynyl-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide and 4-iodoacetophenone were reacted to give the title compound as a light yellow foam (52 mg, 86%).
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C@@H:3]([OH:5])[CH3:4].[H-].[Na+].Cl[C:10]1[CH:11]=[CH:12][C:13]2[CH2:14][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH2:17][O:18][C:19]=2[N:20]=1.O>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH3:4][C@H:3]([O:5][C:10]1[CH:11]=[CH:12][C:13]2[CH2:14][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH2:17][O:18][C:19]=2[N:20]=1)[CH:2]([CH3:6])[CH3:1]
Reactant: CC(C)[C@H](C)O
Reactant: CC(C)(C)OC(=O)N1CCOc2nc(Cl)ccc2C1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)[C@H](C)Oc1ccc2c(n1)OCCN(C(=O)OC(C)(C)C)C2
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 67 %

Procedure:
To a solution of (2S)-3-methylbutan-2-ol (0.38 mL) in toluene (8 mL) was added sodium hydride (0.28 g), and the resulting mixture was stirred at 70° C. for 15 min under a nitrogen atmosphere. A mixture of tert-butyl 8-chloro-2,3-dihydropyrido[3,2-f][1,4]oxazepine-4(5H)-carboxylate (1.0 g), BINAP (0.066 g), Pd2(dba)3 (0.048 g) and toluene (8 mL) was added, and the resulting mixture was stirred at 100° C. for 2 hr under an argon atmosphere. The reaction solution was poured into water, and the resulting product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→40% ethyl acetate/hexane) to give tert-butyl 8-{[(1S)-1,2-dimethylpropyl]oxy}-2,3-dihydropyrido[3,2-f][1,4]oxazepine-4(5H)-carboxylate (0.79 g, 67%) as a white powder.
Reaction SMILES: CS(O[CH2:6][C@H:7]([NH:9][C:10](=[O:22])[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[C:13]([O:20][CH3:21])[CH:12]=1)[CH3:8])(=O)=O.[H-].[Na+]>C1COCC1>[CH3:21][O:20][C:13]1[CH:12]=[C:11]([C:10]([N@@:9]2[CH2:6][CH:7]2[CH3:8])=[O:22])[CH:16]=[CH:15][C:14]=1[N+:17]([O-:19])=[O:18]
Reactant: COc1cc(C(=O)N[C@H](C)COS(C)(=O)=O)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(C(=O)N2CC2C)ccc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 5 h
Yield: 71 %

Procedure:
To a solution of (R)-2-(3-methoxy-4-nitrobenzamido)propyl methanesulfonate (1 equiv) in THF (0.14 M) was added sodium hydride (4 equiv, 60% in mineral oil). The mixture was stirred at 60° C. for 5 h. The reaction was quenched with aqueous ammonium chloride, diluted with ethyl acetate (0.16 M), and then washed with water (0.27 M) and brine (0.27 M). The aqueous layer was extracted with ethyl acetate (0.16 M). The combined organic phase was dried over magnesium sulfate and filtered. The filtrate was concentrated. The crude compound was purified by silica gel chromatography (15% ethyl acetate in petroleum ether) to afford the desired compound (71% yield). MS (ESI) m/z 235.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10](B3OC(C)(C)C(C)(C)O3)=[CH:9][N:8]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1.Cl[C:31]1[N:36]=[C:35]([NH:37][CH:38]([C:44]2([CH3:48])[CH2:47][CH2:46][CH2:45]2)[CH2:39][C:40]([O:42][CH3:43])=[O:41])[C:34]([F:49])=[CH:33][N:32]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>CC1OCCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:49][C:34]1[C:35]([NH:37][CH:38]([C:44]2([CH3:48])[CH2:45][CH2:46][CH2:47]2)[CH2:39][C:40]([O:42][CH3:43])=[O:41])=[N:36][C:31]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([F:1])[CH:3]=3)[N:8]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:21])=[O:22])[CH:9]=2)=[N:32][CH:33]=1
Reactant: COC(=O)CC(Nc1nc(Cl)ncc1F)C1(C)CCC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(F)cnc32)cc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CC1CCCO1
Product: COC(=O)CC(Nc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(F)cc23)ncc1F)C1(C)CCC1
Temperature: 115 °C
Reaction time: 2 h

Procedure:
A solution of 5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine, 7a, (3.31 g, 7.95 mmol), racemic methyl 3-((2-chloro-5-fluoropyrimidin-4-yl)amino)-3-(1-methylcyclobutyl)propanoate, 118a, (2.00 g, 6.63 mmol) and K3PO4 (4.22 g, 20.00 mmol) in 2-MeTHF (253 mL) and water (56 mL) was purged with nitrogen for 0.75 h. XPhos (0.38 g, 0.80 mmol) and Pd2(dba)3 (0.15 g, 0.17 mmol) were added and the reaction mixture was stirred at 115° C. in a sealed tube for 2 hours. The reaction mixture was cooled and the aqueous phase was removed. The organic phase was filtered through a pad of Celite and the mixture was concentrated to dryness. The residue was purified via silica gel chromatography (EtOAc/Hexanes) to afford the desired product: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=2.32 minutes (M+H) 556.44.
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[C:11]([NH:12][C:13](=O)[C:4]2=[N:3][CH:2]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3.C(N(CC)C1C=CC=CC=1)C.C(Cl)[Cl:27].CO>P(Cl)(Cl)(Cl)=O>[Cl:27][C:13]1[C:4]2[N:5]([CH:1]=[CH:2][N:3]=2)[C:6]2[C:11]([N:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: ClCCl
Reactant: O=c1[nH]c2ccccc2n2ccnc12
Solvent: O=P(Cl)(Cl)Cl
Solvent: CO
Solvent: CCN(CC)c1ccccc1
Product: Clc1nc2ccccc2n2ccnc12
Yield: 75 %

Procedure:
Compound 11 (1.4 g, 6.4 mmol) is solubilized in phosphorus oxychloride (24 ml), and N,N-diethylaniline (3.6 ml). The reaction mixture obtained is carried to reflux for approximately 2 h. The product is insoluble in POCl3 even after heating. The reaction is monitored by TLC, eluent: CH2Cl2/MeOH (95/5). TLC shows the presence of the end product, but also the appearance of breakdown products. The reaction mixture is dark brown in colour. The POCl3 is evaporated under vacuum. The residue is cooled in an ice bath before adding a little water and, dropwise, a saturated sodium bicarbonate solution to neutralize POCl3. A light yellow foam and a brown precipitate appear. The solid is isolated by filtration and is recrystallized in methanol. A beige solid (0.97 g, 75%) is obtained; 1H NMR (300 MHz, DMSO-d6) δ: 8.5 (s, 1H, N—CH—C), 8.06 (d, 1H, ArH), 7.56 (s, 1H, C—CH—N), 7.35 (m, 1H, ArH), 7.25 (m, 2H, ArH). Analysis calculated for C10H6N3C1: C, 58.98; H, 2.97; N, 20.64. Experimental: C, 59.12; H, 2.76; N, 20.45.
Reaction SMILES: Br.C([O:4][C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:23]=[C:22]([Br:24])[CH:21]=[C:20]3[C:15]=2[NH:16][C:17](=[O:26])[C:18](=[O:25])[NH:19]3)[CH2:9][CH2:8]1)=[O:6])C.Cl>[OH-].[Na+]>[Br:24][C:22]1[CH:21]=[C:20]2[C:15]([NH:16][C:17](=[O:26])[C:18](=[O:25])[NH:19]2)=[C:14]([CH2:13][N:10]2[CH2:11][CH2:12][CH:7]([C:5]([OH:6])=[O:4])[CH2:8][CH2:9]2)[CH:23]=1
Reactant: CCOC(=O)C1CCN(Cc2cc(Br)cc3[nH]c(=O)c(=O)[nH]c23)CC1
Agent: Br
Agent: Cl
Agent: [Na+]
Product: O=C(O)C1CCN(Cc2cc(Br)cc3[nH]c(=O)c(=O)[nH]c23)CC1

Procedure:
1.28 g (3.12 mmol) of N-(7-bromo-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-ylmethyl)-piperidine-4-carboxylic acid ethyl ester hydrobromide (penultimate compound in Example 2) are stirred at 20° C. for 16 hours in 12 ml of 2N sodium hydroxide solution. The mixture is acidified with 2N hydrochloric acid, and the resulting solid is filtered off and washed with water and diethyl ether. The title compound is obtained in the form of a white solid.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[C:8]([NH:9][CH2:10][CH2:11][O:12][CH3:13])=[N:7][O:6][N:5]=1.[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([F:24])=[C:20]([CH:23]=1)[C:21]#[N:22]>>[C:21]([C:20]1[CH:23]=[C:16]([NH:15][C:3]([C:4]2[C:8]([NH:9][CH2:10][CH2:11][O:12][CH3:13])=[N:7][O:6][N:5]=2)=[N:2][OH:1])[CH:17]=[CH:18][C:19]=1[F:24])#[N:22]
Reactant: COCCNc1nonc1C(Cl)=NO
Reactant: N#Cc1cc(N)ccc1F
Product: COCCNc1nonc1C(=NO)Nc1ccc(F)c(C#N)c1
Yield: 100 %

Procedure:
The desired compound was prepared according to the procedure of Example 13, step A, using N-hydroxy-4-[(2-methoxyethyl)amino]-1,2,5-oxadiazole-3-carboximidoyl chloride [made according to Example 1, steps A through E] and 5-amino-2-fluorobenzonitrile [Aldrich, product #639877] as the starting materials in 100% yield. LCMS for C13H14FN6O3 (M+H)+: m/z=321.0.