Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.[N:45]1C=CC=CC=1.C(=O)(O)[O-].[NH4+]>CS(C)=O.O>[OH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH2:45])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: O=C(O)c1ccc(C[C@@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@H]2O)cc1
Reactant: c1ccncc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)c1ccc(C[C@@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 57.5 %

Procedure:
To a solution of 4-(((1S,2S)-1-hydroxy-2,3-dihydro-1H,1′H-[2,2′-biinden]-2-yl)methyl)benzoic acid (100 mg, 0.26 mmol) in DMSO (5 mL) was added Boc anhydride (69 mg, 0.31 mmol) followed by pyridine (24 mg, 0.26 mmol) and stirred at room temperature for 5 min. Ammonium bicarbonate (62 mg, 0.78 mmol) was added and stirred for additional 1 h. Reaction mixture was poured into water (25 mL) and extracted with ethyl acetate (3×25 mL). The organic layer was washed with brine (25 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by CombiFlash using 20% ethyl acetate in chloroform as an eluent to yield 57 mg (57%) of the title compound as an off white solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.ClC(Cl)(Cl)[C:12]([NH:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[CH:23]=[N:22][CH:21]=[CH:20]2)=[O:13].C1CCN2C(=NCCC2)CC1>CO>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:12]([NH:14][C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:24]=2[CH:23]=[N:22][CH:21]=[CH:20]3)=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(Nc1cccc2ccncc12)C(Cl)(Cl)Cl
Reactant: NCc1ccc(Br)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: O=C(NCc1ccc(Br)cc1)Nc1cccc2ccncc12

Procedure:
The title compound was prepared using 4-bromobenzylamine, the product from Example 57D, DBU and the procedure described in Example 1B. MS (ESI+) m/z 356 (M+H)+; 1H NMR (DMSO-d6) δ 9.52 (s, 1H), 9.15 (s, 1H), 8.49 (d, 1H), 8.11 (d, 1H), 7.77 (d, 1H), 7.67 (t, 1H), 7.55 (m, 3H), 7.32 (d, 2H), 7.25 (t, 1H), 4.34 (d, 2H); Anal. Calcd for C17H14BrN3O.0.25H2O.0.16 MeOH: C, 56.34; H, 4.17; N, 11.49. Found C, 56.32, H, 4.45, N, 11.70.
Reaction SMILES: C([O:5][C:6](=[O:20])[CH2:7][N:8]1[C:12]2=[CH:13][N:14]=[CH:15][CH:16]=[C:11]2[C:10]([C:17](=[O:19])[CH3:18])=[CH:9]1)(C)(C)C.[C:21]([OH:27])([C:23]([F:26])([F:25])[F:24])=[O:22]>C(Cl)Cl>[F:24][C:23]([F:26])([F:25])[C:21]([OH:27])=[O:22].[C:17]([C:10]1[C:11]2[C:12](=[CH:13][N:14]=[CH:15][CH:16]=2)[N:8]([CH2:7][C:6]([OH:20])=[O:5])[CH:9]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)c1cn(CC(=O)OC(C)(C)C)c2cnccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1cn(CC(=O)O)c2cnccc12

Procedure:
A solution of (3-acetyl-pyrrolo[2,3-c]pyridin-1-yl)-acetic acid tert-butyl ester (230 mg, 0.8 mmol) and TFA (0.915 mL, 11.95 mmol) in CH2Cl2 (3.1 mL) was stirred at RT overnight. The reaction mixture was concentrated and the residue was dried under high vacuum. The resulting solid was taken-up in Et2O and filtered to give the desired compound (TFA salt) as beige powder which was used in the next step without purification. MS (UPLC/MS): 219.2 [M+H]+, 217.2 [M−H]−; 1H-NMR (400 MHz, DMSO): δ (ppm): 9.50 (s, 1H), 9.03 (s, 1H), 8.54 (d, 1H), 8.51 (d, 1H), 5.40 (s, 2H), 2.57 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:14][C:15]4[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:9][CH:8]=2)[CH:2]=1.[H][H]>CO.O.[Pt](=O)=O>[NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:14][C:15]4[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:9][CH:8]=2)[CH2:2]1
Reactant: NC(=O)c1cccc2nc(-c3ccc(-c4cccnc4)cc3)oc12
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: O
Solvent: CO
Product: NC(=O)c1cccc2nc(-c3ccc(C4CCCNC4)cc3)oc12
Yield: 9.8 %

Procedure:
2-(4-(Pyridin-3-yl)phenyl)benzo[d]oxazole-7-carboxamide (100 mg, 0.35 mmol) and platinum (IV) oxide monohydrate (55 mg) in methanol (20 mL) was purged with 20 atm of hydrogen at 50° C. for 24 h. Then the mixture was filtered and adjusted to pH=9. The solvent was removed in vacuum. The crude was purified by pre-HPLC. 11 mg of 2-(4-(piperidin-3-yl)phenyl)benzo[d]oxazole-7-carboxamide was obtained, yield: 11%. 1H-NMR (400 MHz, DMSO-d6) δ 1.45 (s, 3H), 1.74-1.77 (m, 2H), 1.89-1.96 (m, 2H), 2.87-2.90 (m, 1H), 3.06-3.09 (m, 2H), 7.85-7.90 (brs, 2H), 7.94-7.96 (d, J=8.0 Hz, 2H), 8.26-8.28 (d, J=8.2 Hz, 2H); LC-MS (ESI) m/z: 316 (M+1)+.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.P(C#N)(=O)(OCC)OCC.[Cl:28][C:29]1[N:38]=[C:37]2[C:32]([CH:33]=[CH:34][C:35]([N:39]3[C:47](=[O:48])[C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[CH:40]3[CH2:49][C:50](O)=[O:51])=[N:36]2)=[C:31]([CH3:53])[CH:30]=1>CN(C)C=O>[Cl:28][C:29]1[N:38]=[C:37]2[C:32]([CH:33]=[CH:34][C:35]([N:39]3[CH:40]([CH2:49][C:50]([N:8]4[CH2:9][CH2:10][C:5]5([O:4][CH2:3][CH2:2][O:1]5)[CH2:6][CH2:7]4)=[O:51])[C:41]4[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:47]3=[O:48])=[N:36]2)=[C:31]([CH3:53])[CH:30]=1
Reactant: Cc1cc(Cl)nc2nc(N3C(=O)c4ccccc4C3CC(=O)O)ccc12
Reactant: C1CC2(CCN1)OCCO2
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(Cl)nc2nc(N3C(=O)c4ccccc4C3CC(=O)N3CCC4(CC3)OCCO4)ccc12
Temperature: 0 °C
Yield: 90.2 %

Procedure:
With ice-cooling and stirring, 1.6 g of 1,4-dioxa-8-azaspiro[4.5]decane, 2 ml of triethylamine and 2.2 g of diethyl phosphorocyanidate were successively added to a solution of 3.5 g of 2-(7-chloro-5-methyl-1,8-naphthyridin-2-yl)-3-oxoisoindoline-1-acetic acid in 30 ml of dimethylformamide. The mixture was stirred with ice-cooling for an additional 2 hours and 200 ml of ice-water was added thereto. The mixture was allowed to stand, and the resulting crystalline precipitate was collected by filtration, washed with water and dried. Recrystallization from dichloromethane-ether (1:4) gave 4.23 g of colorless crystals melting at 259°-262° C.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]([CH3:17])[CH3:16])=[CH:11][C:10]=2[CH:18]=[CH2:19])=[CH:5][CH:4]=1.[O:20]=[C:21]1[CH2:25][N:24]([C:26]([O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])=[O:27])[C@H:23]([C:35]([O:37][CH3:38])=[O:36])[CH2:22]1>C1COCC1.C(Cl)Cl>[CH3:16][N:15]([CH3:17])[C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:7]=[CH:8][C:3]([C@@:21]3([OH:20])[CH2:25][N:24]([C:26]([O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:32])[CH3:33])=[O:27])[C@H:23]([C:35]([O:37][CH3:38])=[O:36])[CH2:22]3)=[CH:4][CH:5]=2)=[C:10]([CH:18]=[CH2:19])[CH:11]=1
Reactant: COC(=O)[C@@H]1CC(=O)CN1C(=O)OCC[Si](C)(C)C
Reactant: C=Cc1cc(N(C)C)ccc1-c1ccc(Br)cc1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=Cc1cc(N(C)C)ccc1-c1ccc([C@]2(O)C[C@@H](C(=O)OC)N(C(=O)OCC[Si](C)(C)C)C2)cc1
Reaction time: 0.5 h
Yield: 26.6 %

Procedure:
Magnesium (62 mg, 2.55 mmol) was stirred in a round bottom flask under N2 for 15 min. to cause scratching of the surface of the magnesium turnings. 10 mL of THF was added to the magnesium turnings and stirred for an additional 30 min. 4′-bromo-N,N-dimethyl-2-vinylbiphenyl-4-amine (735 mg, 2.432 mmol) in THF (20 mL), was added dropwise at reflux with vigorous stirring. The Grignard solution was added to a solution of (S)-2-methyl 1-(2-(trimethylsilyl)ethyl) 4-oxopyrrolidine-1,2-dicarboxylate (699 mg, 2.432 mmol) in DCM (20 mL) at r.t. and stirred for 1 hr and then quenched with sat. NH4Cl solution. The aqueous layer was extracted with DCM and the combined organics were dried, filtered and evaporated to give crude material. The crude material was purified by flash chromatography on the Biotage (10-40% EtOAc:Hex) to give (2S,4R)-2-methyl 1-(2-(trimethylsilyl)ethyl) 4-(4′-(dimethylamino)-2′-vinylbiphenyl-4-yl)-4-hydroxypyrrolidine-1,2-dicarboxylate (330 mg, 0.646 mmol, 27% yield) as a yellow foam. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.04 (s, 9H) 0.99-1.11 (m, 2H) 2.34-2.52 (m, 1H) 2.62-2.81 (m, 1H) 3.00-3.07 (m, 6H) 3.68-3.81 (m, 1H) 3.82-3.89 (m, 3H) 4.17-4.34 (m, 3H) 4.49-4.68 (m, 1H) 5.19 (dd, J=11.04, 1.25 Hz, 1H) 5.70 (dd, J=17.57, 1.25 Hz, 1H) 6.67-6.80 (m, 2H) 6.96 (d, J=2.26 Hz, 1H) 7.16-7.22 (m, 1H) 7.34 (m, 2H) 7.49 (m, J=8.28 Hz, 2H). LCMS: rt=1.71 min. [M+H]+=511; Phenomenex-Luna C-18 (5μ) (3.0×50 mm); Solvent A=10% acetonitrile—90% water—0.1% TFA, Solvent B=90% acetonitrile—10% water—0.1% TFA; gradient 0% to 100% solvent B over 2 min. and then hold for 1 min.; 4 mL/min; inj. vol.=5 uL; wavelength=220.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[C:8]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[N:20][S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:23])=[O:22])SC)=[CH:12][CH:11]=1)#[N:9]>O.C(O)C>[C:24]1([S:21]([N:20]=[C:17]([NH:16][C:13]2[CH:12]=[CH:11][C:10]([C:8]#[N:9])=[CH:15][CH:14]=2)[NH:1][CH2:2][C:3]([OH:5])=[O:4])(=[O:23])=[O:22])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: NCC(=O)O
Reactant: CSC(=NS(=O)(=O)c1ccccc1)Nc1ccc(C#N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(NC(=NS(=O)(=O)c2ccccc2)NCC(=O)O)cc1
Reaction time: 7 h
Yield: 52 %

Procedure:
A mixture of 0.57 g (7.6 mmoles) of glycine and 0.3 g (7.6 mmoles) of sodium hydroxide in 3 cm3 of water and 2.5 (7.6 mmoles) of N-(4-cyanophenyl)-N'-phenylsulfonyl-S-methylisothiourea in 30 cm3 of 95% ethanol is heated to boiling for 7 hours. After cooling, the precipitate obtained is filtered and dissolved in 20 cm3 of 1N sodium hydroxide solution. The solution obtained is washed with dichloromethane (3×10 cm3) and ethyl acetate (2×10 cm3) and is then acidified to pH 3 with a 6N HCl solution. After cooling, precipitate forms and is filtered, washed with water (2×5 cm3) and dried in vacuo to give 1.4 g (yield 52%) of N-[phenylsulfonylimino(4-cyanophenylamino)methyl]-2-aminoethanoic acid having a melting point of 133° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(#N)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:21]2[CH2:20][CH2:19][N:18]([C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])[CH2:23][CH2:22]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Yield: 99.6 %

Procedure:
A mixture of 2-bromo-5-nitro-pyridine (1.719 g, 8.468 mmol), piperazine-1-carboxylic acid tert-butyl ester (1.58 g, 8.468 mmol), triethylamine (3.54 mL, 25.4 mmol) in acetonitrile (6 mL) is heated at 86 C for 2 h. After it is evaporated, the residue is dissolved in methylene chloride, and washed with saturated sodium bicarbonate solution. The organic layer is evaporated to yield 2.6 g (99%) of the title compound as a pale-yellow solid. NMR (CDCl3) showed it is pure.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[O:13]=[C:14]1[CH2:18][CH2:17][C:16]2([CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[O:15]1.[F:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Br)=[CH:34][CH:33]=1>C1COCC1>[O:13]=[C:14]1[CH:18]([CH2:36][C:35]2[CH:38]=[CH:39][C:32]([F:31])=[CH:33][CH:34]=2)[CH2:17][C:16]2([CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[O:15]1
Reactant: Fc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(=O)O2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(Cc1ccc(F)cc1)C(=O)O2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
A solution of diisopropyl amine (0.36 mL, 2.6 mmol) in 7.5 mL dry THF was cooled to −78° C. and n-butyllithium (1.5 mL, 1.6 M in hexane, 2.4 mmol) was added. The mixture was warmed to 0° C. for 15 min then recooled to −78° C. A solution of 2-oxo-8-(t-Butoxycarbonyl)-8-aza-1-oxaspiro[4.5]decane (510 mg, 2.0 mmol, from Step B) in 2 mL THF was added dropwise. After 30 min at −78° C. 4-fluorobenzyl bromide (0.32 mL, 2.6 mmol) was added and after 30 min the mixture was warmed to room temperature and quenched with sat'd ammonium chloride. The mixture was extracted with ethyl acetate and the organic portion was dried over sodium sulfate and concentrated. Flash chromatography (3/1 hexane/EtOAc) afforded 510 mg (70%) of the desired product. 1H NMR (400 MHz, CDCl3). δ 1.44 (s, 9H), 1.51-1.81 (5H), 2.03-2.19 (m, 1H), 2.76-2.81 (dd, 1H), 2.99-3.04 (m, 1H), 3.18-3.3 (m, 3H), 3.72-3.81 (m, 2H), 6.97-7.03 (m, 2H), 7.11-7.18 (m, 2H). The lactone was separated into its enantiomers by semiprep chiral HPLC (chiralpak AD, 9/1 hexane/IPA→8/1 hexane/IPA) to afford the two enantiomers (enantiomer A, 92% ee and enantiomer B, 73% ee). The two enantiomers were converted to the spiro tetrahydrofuran derivatives as described below for enantiomer B.
Reaction SMILES: CN(CCN(C)C)C.[NH:9]1[CH:16]=[CH:15][C:13]([NH2:14])=[N:12][C:10]1=[O:11].[F:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>CO.O.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[NH2:14][C:13]1[CH:15]=[CH:16][N:9]([C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=2)[C:10](=[O:11])[N:12]=1
Reactant: Nc1cc[nH]c(=O)n1
Reactant: OB(O)c1ccc(F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CN(C)CCN(C)C
Solvent: O
Solvent: CO
Product: Nc1ccn(-c2ccc(F)cc2)c(=O)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 321.7 %

Procedure:
TMEDA (8 mL, 54 mmol) was added to a stirred suspension of cytosine (3 g, 27 mmol), 4-fluorophenylboronic acid (7.55 g, 5 mmol) and copper(II)acetate monohydrate (5.44 g, 27 mmol) in a mixture of MeOH (960 mL) and H2O (240 mL). The mixture was stirred at RT for 16 hours. The solvents were evaporated in vacuo and the crude product purified by open column chromatography (silica; MeOH in DCM with a gradient of 0/100 to 100/0). The desired fractions were collected and the solvents evaporated in vacuo. The product was triturated with MeOH and DCM and the solid formed filtered and dried in vacuo to yield 4-amino-1-(4-fluoro-phenyl)-1H-pyrimidin-2-one (3.3 g, 60% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH2:8].[NH2:9][C:10]1[C:11]([C:25](O)=[O:26])=[N:12][C:13]([C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[C:14]([F:16])[CH:15]=1.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN1C(=O)CCC1>[NH2:9][C:10]1[C:11]([C:25]([NH:8][C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[O:26])=[N:12][C:13]([C:17]2[C:18]([F:24])=[CH:19][CH:20]=[CH:21][C:22]=2[F:23])=[C:14]([F:16])[CH:15]=1
Reactant: Nc1cnccc1Cl
Reactant: Nc1cc(F)c(-c2c(F)cccc2F)nc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CN1CCCC1=O
Product: Nc1cc(F)c(-c2c(F)cccc2F)nc1C(=O)Nc1cnccc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 14 %

Procedure:
To a solution of 4-chloropyridin-3-amine (1.0 equiv.) and 3-amino-6-(2,6-difluorophenyl)-5-fluoropicolinic acid (1.0 equiv.) in NMP (1 M) was added HOAt and EDCI sequentially. The reaction mixture was stirred at room temperature for 2 days. The crude reaction was purified by prep HPLC to give 3-amino-N-(4-chloropyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide (14%). LCMS (m/z): 379.0 (MH+); LC Rt=3.49 min
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.C1(C)C=CC=CC=1.ClS([N:26]=[C:27]=[O:28])(=O)=O>O>[Cl:1][C:2]1[C:7]([NH:8][C:27]([NH2:26])=[O:28])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Nc1c(Cl)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: NC(=O)Nc1c(Cl)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 4 h

Procedure:
370 Parts of 6-chloro-2,4-dinitroaniline are stirred for 4 hours at 80° C. in 2600 parts of toluene with 312 parts of chlorosulfonyl isocyanate. At 25° C., 360 parts of water are added to the resulting suspension of N-6-chloro-2,4-dinitrophenyl-N'-chlorosulfonyl urea without intermediate isolation, and the mixture is saponified at 60° C. within 4 hours to yield 6-chloro-2,4-dinitrophenyl urea. After diluting said mixture with water, it is neutralized with 33% sodium hydroxide solution, filtered while hot, and the product is thoroughly washed with hot toluene and water. After drying in vacuo, there are obtained 383 parts of 6-chloro-2,4-dinitrophenyl urea having a melting point of from 219° to 221° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:25][C:26]([OH:28])=O)[C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:29]([NH:31][CH2:32][CH3:33])[CH3:30]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)[CH2:25][C:26]([N:31]([CH2:32][CH3:33])[CH2:29][CH3:30])=[O:28])(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCNCC
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccc3ncccc3c2)cc1
Product: CCN(CC)C(=O)CN(c1ccc2ncccc2c1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-quinolin-6-yl-amino]-acetic acid with diethylamine
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][C:11](=[O:13])[NH2:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:17][C@@H:18]1[CH2:42][CH2:41][C@@:40]2([CH3:43])[CH:20]([CH2:21][CH2:22][C@@H:23]3[C@@H:39]2[CH2:38][CH2:37][C@@:36]2([CH3:44])[C@H:24]3[CH2:25][CH2:26][C@@H:27]2[C@H:28]([CH3:35])[CH2:29][CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:19]1>>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([NH:17][C@@H:18]1[CH2:42][CH2:41][C@@:40]2([CH3:43])[CH:20]([CH2:21][CH2:22][C@@H:23]3[C@@H:39]2[CH2:38][CH2:37][C@@:36]2([CH3:44])[C@H:24]3[CH2:25][CH2:26][C@@H:27]2[C@H:28]([CH3:35])[CH2:29][CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:19]1)=[O:16])[CH2:10][C:11](=[O:13])[NH2:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)C(=O)O
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4C[C@H](N)CC[C@]4(C)[C@H]3CC[C@]12C
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 56 %

Procedure:
By using N-tert-butyloxycarbonyl-L-asparagine (464 mg, 2.00 mmol) and 3α-aminocholestane (777 mg, 2.00 mmol), the title compound was obtained in the same manner as in Synthetic Example BB1 (670 mg, yield; 56%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:19]=[C:13]([C:14]([O:16][CH:17]=[CH2:18])=[O:15])[C:12]([OH:20])=[CH:11][CH:10]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:22].Cl>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:19]=[C:13]([C:14]([O:16][CH:17]([Cl:22])[CH3:18])=[O:15])[C:12]([OH:20])=[CH:11][CH:10]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: C=COC(=O)c1cc(-c2ccc(F)cc2F)ccc1O
Agent: Cl
Product: CC(Cl)OC(=O)c1cc(-c2ccc(F)cc2F)ccc1O
Reaction time: 1 h

Procedure:
To a mixture of vinyl 5-(2,4-difluorophenyl)salicylate (15 g) and 0.1 g dry PCl5, HCl gas is passed for about one hour at about 120°-125° C. Upon cooling, the crude product crystallizes and is collected by filtration. Recrystallization from methanol yields pure 1-chloroethyl 5-(2,4-difluorophenyl)salicylate.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:25]=3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:11].[S:32](N)([NH2:35])(=[O:34])=[O:33]>O1CCOCC1>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:27][CH2:28][N:29]([S:32]([NH2:35])(=[O:34])=[O:33])[CH2:30][CH2:31]4)[CH:25]=3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:11]
Reactant: NS(N)(=O)=O
Reactant: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(-c3cnn(C4CCNCC4)c3)cc12
Solvent: C1COCCO1
Product: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(-c3cnn(C4CCN(S(N)(=O)=O)CC4)c3)cc12
Temperature: 90 °C

Procedure:
A mixture of 3-[1-(2,6-dichloro-3-fluorophenyl)ethyl]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine (8.0 mg, 0.0174 mmol), sulfamide (3.35 mg, 0.0349 mmol) and dioxane (2 mL) was heated to 90° C. overnight in a sealed tube. The solution was concentrated in vacuo, redissolved in MeOH and purified via HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.89 (d, J=7.1 Hz, 3 H), 2.09-2.25 (m, 4 H), 2.76-2.91 (m, 2H), 3.78 (d, J=12.4 Hz, 2 H), 4.30 (dt, J=10.4, 5.3 Hz, 1 H), 5.29 (q, J=7.4 Hz, 1 H), 7.15-7.23 (m, 1 H), 7.36 (d, J=1.5 Hz, 1 H), 7.38-7.53 (m, 2 H), 7.58 (s, 1 H), 7.92 (s, 1 H), 8.32 (d, J=1.8 Hz, 1 H). MS (ES+): m/z 537.02 (100) [MH+]. HPLC: tR=3.36 min (ZQ3, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][C:24]([OH:26])=O)[CH2:19][CH2:18]3)=[O:16])[N:13]=2)=[O:7])=[CH:4][CH:3]=1.[NH2:29][CH:30]1[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]1>C1COCC1>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][C:24](=[O:26])[NH:29][CH:30]4[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]4)[CH2:19][CH2:18]3)=[O:16])[N:13]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CN1CCC(N)CC1
Reactant: O=C(O)CN1CCN(C(=O)Cc2csc(NC(=O)c3ccc(Cl)cc3)n2)CC1
Solvent: C1CCOC1
Product: CN1CCC(NC(=O)CN2CCN(C(=O)Cc3csc(NC(=O)c4ccc(Cl)cc4)n3)CC2)CC1

Procedure:
In analogy to example 22.3, (4-{2-[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetyl}-piperazin-1-yl)-acetic acid (example 22.2) was coupled with 4-amino-1-methylpiperidine, using general method A, using THF instead of DMF as solvent, to give 4-chloro-N-[4-(2-{4-[(1-methyl-piperidin-4-ylcarbamoyl)-methyl]-piperazin-1-yl}-2-oxo-ethyl)-thiazol-2-yl]-benzamide. White solid. MS 519.3 ([M+H]+)
Reaction SMILES: [C:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([OH:3])=[O:2].[C:11]1(=[O:17])[O:16][C:14](=[O:15])[CH:13]=[CH:12]1>>[C:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:11](=[O:17])/[CH:12]=[CH:13]\[C:14]([OH:16])=[O:15])=[CH:6][CH:5]=1)([OH:3])=[O:2]
Reactant: O=C1C=CC(=O)O1
Reactant: Nc1ccc(C(=O)O)cc1
Product: O=C(O)/C=C\C(=O)Nc1ccc(C(=O)O)cc1

Procedure:
Similarly, equimolar amounts of p-carboxy aniline and maleic anhydride reacted to produce N-(p-carboxyphenyl)maleamic acid.
Reaction SMILES: [CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[CH:14])=[C:8]3[N:7]=[C:6]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH:5]=2)[CH2:3][CH2:2]1.[OH:25][CH2:26][C:27]([NH:30][S:31]([C:34]1[S:38][C:37](Cl)=[N:36][CH:35]=1)(=[O:33])=[O:32])([CH3:29])[CH3:28]>>[OH:25][CH2:26][C:27]([NH:30][S:31]([C:34]1[S:38][C:37]([C:14]#[C:13][C:12]2[CH:11]=[N:10][N:9]3[C:4]([CH:1]4[CH2:3][CH2:2]4)=[CH:5][C:6]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=4)=[N:7][C:8]=23)=[N:36][CH:35]=1)(=[O:33])=[O:32])([CH3:29])[CH3:28]
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CC(C)(CO)NS(=O)(=O)c1cnc(Cl)s1
Product: CC(C)(CO)NS(=O)(=O)c1cnc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 7-cyclopropyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.7) (82 mg, 0.25 mmol) and 2-chloro-thiazole-5-sulfonic acid(2-hydroxy-1,1-dimethyl-ethyl)-amide (68 mg, 0.25 mmol) (Example B.14) according to general procedure II. Obtained as a yellow solid (24 mg, 17%). MS (ISP) 562.0 [(M+H)+]; mp 243–245° C.