Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]3[N:16]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:17]=[CH:18][C:13]3=[C:12]([N:24]3[CH2:29][C@H:28]4[CH2:30][C@@H:25]3[CH2:26][O:27]4)[N:11]=2)=[CH:6][CH:5]=1)([O-])=O>O1CCCC1.O>[C@@H:28]12[CH2:30][C@@H:25]([N:24]([C:12]3[N:11]=[C:10]([C:7]4[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=4)[N:15]=[C:14]4[N:16]([CH2:19][C:20]([F:22])([F:23])[F:21])[N:17]=[CH:18][C:13]=34)[CH2:29]1)[CH2:26][O:27]2
Reactant: O=[N+]([O-])c1ccc(-c2nc(N3C[C@H]4C[C@@H]3CO4)c3cnn(CC(F)(F)F)c3n2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(-c2nc(N3C[C@H]4C[C@@H]3CO4)c3cnn(CC(F)(F)F)c3n2)cc1
Reaction time: 8 h
Yield: 93.9 %

Procedure:
A suspension of (1R,4R)-5-(6-(4-nitrophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane (0.50 g, 1.2 mmol) in tetrahydrofuran (20 mL) and water (5 mL) was degassed by the addition of crushed dry ice and then treated with 10% palladium on carbon (50 mg). The resulting suspension was evacuated under weak vacuum and then filled with hydrogen gas (balloon). This evacuation/fill cycle was performed three more times and on the final iteration, the mixture was left to stir overnight under a hydrogen filled balloon. The mixture was filtered through a pad of diatomaceous earth, eluting with methanol. The filtrate was concentrated under reduced pressure to afford 4-(4-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline as a gray foam (0.44 g, 93%). MS (ES+): 391.2 (M+H)+
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH3:23])[C:20](O)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH2:48]([NH:55][C@@H:56]([CH3:64])[CH:57]([O:61][CH2:62][CH3:63])[O:58][CH2:59][CH3:60])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1.CCN(C(C)C)C(C)C>ClCCl.C(OCC)(=O)C>[CH2:62]([O:61][CH:57]([O:58][CH2:59][CH3:60])[C@@H:56]([N:55]([CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C:20](=[O:21])[C@@H:19]([NH:18][C:16](=[O:17])[O:15][CH2:14][CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH3:23])[CH3:64])[CH3:63]
Reactant: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CCOC(OCC)[C@H](C)NCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(OCC)[C@H](C)N(Cc1ccccc1)C(=O)[C@H](C)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.2 %

Procedure:
To a solution of (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)propanoic acid 68 mg (0.22 mmol) and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate 84 mg (0.22 mmol) in dichloromethane 1 ml, a solution of (S)—N-benzyl-1,1-diethoxypropan-2-amine (Compound IV-15) 47 mg (0.2 mmol) and N,N′-diisopropylethylamine 38 ml (0.22 mmol) in dichloromethane 1 ml was added and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate 50 ml and washed with saturated aqueous sodium bicarbonate 50 ml, water 50 ml and brine 50 ml. The organic phase was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified on silica gel column chromatography (n-hexane:ethyl acetate=9:1 to 7:3) to obtain the title compound 48 mg (45%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11]([CH3:14])([CH3:13])[CH2:10][CH:9]1[C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:19]1[C:23](=[O:24])[CH2:22][CH2:21][C:20]1=[O:25].C(N=C=NC(C)C)(C)C>C1COCC1>[O:25]=[C:20]1[CH2:21][CH2:22][C:23](=[O:24])[N:19]1[O:16][C:15]([CH:9]1[CH2:10][C:11]([CH3:14])([CH3:13])[CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:17]
Reactant: O=C1CCC(=O)N1O
Reactant: CC1(C)CC(C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: CC1(C)CC(C(=O)ON2C(=O)CCC2=O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.7 %

Procedure:
A solution of 4,4-dimethyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butylester (2.0 g, 8.22 mmol) in THF (20 mL) was cooled to 0° C. To the cold solution was added N-hydroxysuccinimide (1.2 g, 10.4 mmol) and diisopropylcarbodiimide (1.32 g, 10.4 mmol). Cooling was removed and the mixture stirred for 3 hours at room temperature. The urea was filtered off, washed with diethylether and the filtrates were concentrated. The residue was partitioned between ethyl acetate and cold water; organic phases were washed with cold brine, combined, dried with MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica, heptane/ethyl acetate 9:1) to give the title compound (1.95 g, 70%) as colorless oil; MS (ESI) 341.1 [MH+].
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:20])[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[C:6]2[N:5]=[C:4]([CH3:21])[C:3]=1[CH2:22][CH2:23]Cl.NC(N)=[S:27].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[C:16]1([CH3:17])[CH:15]=[C:14]([CH3:18])[CH:13]=[C:12]([CH3:19])[C:11]=1[C:10]1[C:9]([CH3:20])=[N:8][N:7]2[C:2]3[S:27][CH2:23][CH2:22][C:3]=3[C:4]([CH3:21])=[N:5][C:6]=12
Reactant: Cc1cc(C)c(-c2c(C)nn3c(Cl)c(CCCl)c(C)nc23)c(C)c1
Reactant: NC(N)=S
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(C)c(-c2c(C)nn3c4c(c(C)nc23)CCS4)c(C)c1
Yield: 97.7 %

Procedure:
A solution of 7-chloro-6-(2-chloroethyl)-3-mesityl-2,5-dimethylpyrazolo[1,5-a]pyrimidine (500 mg,1.38 mmol), thiourea (105 mg, 1.38 mmol)and sodium carbonate (180 mg, 1.73 mmol) in ethanol (10 mL) was heated under reflux for one hour. After evaporating, water was added and the resulting crystals were collected by filtration. The crystals were washed with water, to give the title compound (436 mg) as white crystals.
Reaction SMILES: N(OCCC(C)C)=O.N[C:10]1[C:15]([C:16]#[N:17])=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][OH:27])=[CH:20][CH:19]=2)[C:13]([C:28]#[N:29])=[C:12]([O:30][CH2:31][C:32]2[N:33]=[C:34]([C:37]3[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=3)[O:35][CH:36]=2)[N:11]=1.[ClH:44]>C(#N)C.[Cu](Cl)Cl>[Cl:44][C:10]1[C:15]([C:16]#[N:17])=[C:14]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][OH:27])=[CH:22][CH:23]=2)[C:13]([C:28]#[N:29])=[C:12]([O:30][CH2:31][C:32]2[N:33]=[C:34]([C:37]3[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=3)[O:35][CH:36]=2)[N:11]=1
Reactant: Cl
Reactant: N#Cc1c(N)nc(OCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: N#Cc1c(Cl)nc(OCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
78 mg (0.67 mmol) of isopentyl nitrite and 90 mg (0.67 mmol) of copper(II) chloride were initially charged in 8.5 ml of acetonitrile, and 72 mg (0.64 mmol) of the compound from Example 49A were added. The reaction mixture was stirred at 60° C. for 3 h. 8.5 ml of 1N hydrochloric acid were added to the reaction solution. The aqueous phase was extracted twice with in each case 20 ml of ethyl acetate, and the combined organic phases were dried over magnesium sulfate. After removal of the solvent on a rotary evaporator, the residue was dried under reduced pressure and used without further purification for the subsequent reaction.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.N1C=CC=CC=1.Cl[C:18]([O:20][CH2:21][C:22]([Cl:25])([Cl:24])[Cl:23])=[O:19].O>O1CCCC1>[NH:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][C:18](=[O:19])[O:20][CH2:21][C:22]([Cl:25])([Cl:24])[Cl:23])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1ccc2[nH]ccc2c1
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(Nc1ccc2[nH]ccc2c1)OCC(Cl)(Cl)Cl
Yield: 14.3 %

Procedure:
To a solution of 5-aminoindole (1.00 g, 7.57 mmol) and pyridine (0.720 ml, 9.08 mmol) in tetrahydrofuran (25 ml) was added, under ice-cooling, 2,2,2-trichloroethyl chloroformate (1.26 ml, 9.08 mmol), and the mixture was stirred at room temperature for 1 hour and half. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by high performance liquid chromatography (YMC HPLC Column eluted with 10% to 100% Liquid A; Liquid A: a 0.1% solution of trifluoroacetic acid in acetonitrile; Liquid B: an aqueous 0.1% trifluoroacetic acid solution) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 334 mg (14.3%) of the desired product as a solid.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1.[CH3:17][C:18]1[NH:19][C:20]2[C:25]([CH:26]=1)=[CH:24][C:23]([OH:27])=[CH:22][CH:21]=2.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:17][C:18]1[NH:19][C:20]2[C:25]([CH:26]=1)=[CH:24][C:23]([O:27][C:2]1[CH:3]=[CH:4][C:5]3[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]4[CH2:16][CH2:15]4)=[O:13])[N:10]=3)[N:7]=1)=[CH:22][CH:21]=2
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Reactant: Cc1cc2cc(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2[nH]1
Yield: 19.4 %

Procedure:
Using N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (272 mg, 0.830 mmol), 2-methyl-1H-indole-5-ol (244 mg, 1.66 mmol), potassium carbonate (344 mg, 2.49 mmol) and N,N-dimethylformamide (3.0 mL) as starting materials and in the same manner as in Example 95, the title compound (56 mg, 19%) was obtained as a white powder.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([CH:28]=[CH:29][CH:30]=3)[C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)=[O:16])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:31]1([C:34](Cl)=[O:35])[CH2:33][CH2:32]1.O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH:31]1([C:34]([NH:1][C:2]2[S:3][C:4]3[CH:10]=[C:9]([O:11][C:12]4[CH:13]=[C:14]([CH:28]=[CH:29][CH:30]=4)[C:15]([NH:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:25])[F:26])[CH:19]=4)=[O:16])[CH:8]=[CH:7][C:5]=3[N:6]=2)=[O:35])[CH2:33][CH2:32]1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1nc2ccc(Oc3cccc(C(=O)Nc4cccc(C(F)(F)F)c4)c3)cc2s1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1cccc(Oc2ccc3nc(NC(=O)C4CC4)sc3c2)c1
Yield: 68.3 %

Procedure:
A solution of 3-[(2-amino-1,3-benzothiazol-6-yl)oxy]-N-[3-(trifluoromethyl)phenyl]benzamide (429 mg, 1.00 mmol), cyclopropanecarbonyl chloride (525 mg, 5.0 mmol) and N,N-dimethylpyridine-4-amine (610 mg, 5.00 mmol) in pyridine (5 mL) was stirred at room temperature for 2 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluent:hexane/ethyl acetate=1:1), and triturated with diethyl ether to give the title compound (340 mg, 68%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]4[C:19](=[O:24])[N:20](C)[C:21](=[O:22])[C:14]=34)=[CH:11][N:10]([CH3:25])[N:9]=2)=[CH:4][CH:3]=1.[OH-].[NH4+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]4[C:19](=[O:24])[NH:20][C:21](=[O:22])[C:14]=34)=[CH:11][N:10]([CH3:25])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CN1C(=O)c2nccc(-c3cn(C)nc3-c3ccc(F)cc3)c2C1=O
Agent: [NH4+]
Agent: [OH-]
Product: Cn1cc(-c2ccnc3c2C(=O)NC3=O)c(-c2ccc(F)cc2)n1
Temperature: 120 °C

Procedure:
4-(3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-6-methyl-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione (intermediate from Example 1, step 5, 190 mg, 0.588 mmol) and 28-30% aqueous ammonium hydroxide (4 mL) were heated to a vigorous reflux for 30 min and then concentrated. The residue was dissolved in 1:1 acetic acid/acetic anhydride (20 mL) and heated at 120° C. for 2 hr and concentrated. The residue was dissolve in EtOAc and run through a short silica gel plug to afford 176 mg (92%) of Ex 4-Step 1 product as a white solid which was used without further purification: LCMS m/z 323.1 (M+1); 1H NMR (400 MHz, CDCl3) δ 8.63 (d, J=5.2, 1H), 8.15 (s, 1H), 7.37 (dd, J=8.8, 5.5, 2H), 7.17 (d, J=5; 3, 1H), 7.04 (dd, J=8.6, 8.6, 2H), 4.01 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([C:11]([F:14])([F:13])[F:12])[N:3]=1.[H][H]>C(OCC)(=O)C.[Pt](=O)=O>[NH2:8][C:7]1[C:2]([Cl:1])=[N:3][C:4]([C:11]([F:13])([F:12])[F:14])=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(C(F)(F)F)nc1Cl
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: Nc1ccc(C(F)(F)F)nc1Cl
Yield: 100 %

Procedure:
2-Chloro-3-nitro-6-trifluoromethylpyridine (22.7 g, 0.10 mol) and platinum(IV) oxide (500 mg) in ethyl acetate (500 ml) were hydrogenated at 20 psi hydrogen for 2 hrs, then the catalyst was removed by filtration. The filtrate was concentrated to give the product as a tan solid (19.5 g, 0.1 mol, 99% yield).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[C:13]([NH:15][CH3:16])[CH:12]=[CH:11][C:10]=1[C:17]([O:19][CH3:20])=[O:18])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([O:23][C:24]([N:26]=[C:27]=[S:28])=[O:25])[CH3:22]>CN(C=O)C.C(OCC)(=O)C>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[C:13]([NH:15][CH2:16][C:27]([NH:26][C:24]([O:23][CH2:21][CH3:22])=[O:25])=[S:28])[CH:12]=[CH:11][C:10]=1[C:17]([O:19][CH3:20])=[O:18])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)N=C=S
Reactant: CNc1ccc(C(=O)OC)c(S(=O)(=O)NC(C)(C)C)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)NC(=S)CNc1ccc(C(=O)OC)c(S(=O)(=O)NC(C)(C)C)c1
Yield: 75 %

Procedure:
1.20 g (4.0 mmol) of N-tert-butyl-2-methoxycarbonyl-5-methylaminobenzenesulfonamide is dissolved in 5 ml of anhydrous DMF, and 0.60 g (4.3 mmol) of 95% strength ethoxycarbonyl isothiocyanate is added. After 3 h at room temperature the mixture is taken up in ethyl acetate and washed with 1N hydrochloric acid and water. The organic phase is dried over magnesium sulfate and the solvent is removed by distillation. The residue is taken up in a little ethyl acetate and precipitated with heptane at -25° C. The precipitate is filtered off with suction and dried to give 1.29 g (75% of theory) of colorless N-tert-butyl-5-[N-(ethoxycarbonylaminothiocarbonyl)methylamino]-2-methoxycarbonylbenzenesulfonamide. m.p.: 110° C.
Reaction SMILES: Cl.[NH2:2][OH:3].C(N(CC)CC)C.[Br:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[C:17]([C:22]#[N:23])[CH:16]=[CH:15]2>C(O)C>[Br:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[C:17]([C:22]([NH:2][OH:3])=[NH:23])[CH:16]=[CH:15]2
Reactant: N#Cc1ccc2cc(Br)ccc2c1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: N=C(NO)c1ccc2cc(Br)ccc2c1
Temperature: 25 °C

Procedure:
2.48 g hydroxylamine-hydrochloride and 5.68 ml triethylamine are added to 4.10 g of 6-bromo-2-cyano-naphthalene in 100 ml of ethanol and the reaction mixture is refluxed for four hours. After cooling to ambient temperature the solvent is distilled off in vacuo using the rotary evaporator and the flask residue is divided between water and ethyl acetate. The aqueous phase is extracted with ethyl acetate and the combined organic phases are dried on magnesium sulphate and evaporated down.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]2[C:15]([C:18]3[CH:19]=[C:20]([NH:24][CH:25]4[CH2:30][CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]4)[CH:21]=[N:22][CH:23]=3)=[CH:16][NH:17][C:12]2=[CH:11][CH:10]=1.Cl.CC(O)C>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]2[C:15]([C:18]3[CH:19]=[C:20]([NH:24][CH:25]4[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]4)[CH:21]=[N:22][CH:23]=3)=[CH:16][NH:17][C:12]2=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(Nc2cncc(-c3c[nH]c4ccc(-c5c(F)cccc5F)nc34)c2)C1
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: Fc1cccc(F)c1-c1ccc2[nH]cc(-c3cncc(NC4CCCNC4)c3)c2n1
Temperature: 23 °C

Procedure:
A solution of tert-butyl 3-(5-(5-(2,6-difluorophenyl)-1-tosyl-1H-pyrrolo[3,2-b]pyridin-3-yl)pyridin-3-ylamino)piperidine-1-carboxylate (33 mg, 0.050 mmol) in THF (1 mL) was treated with NaOH 10N (0.050 mL, 0.500 mmol). The reaction was heated to reflux at 80° C. After 4 h, the solution was cooled to 23° C., concentrated in vacuo and purified by silica gel chromatography (eluent: 1-6% MeOH/DCM), affording tert-butyl 3-(5-(5-(2,6-difluorophenyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)pyridin-3-ylamino)piperidine-1-carboxylate (21 mg, 83%). MS (ESI, pos. ion) m/z: 506.3 (M+1) A solution of tert-butyl 3-(5-(5-(2,6-difluorophenyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)pyridin-3-ylamino)piperidine-1-carboxylate (21 mg, 0.042 mmol) in MeOH (1 mL) was treated with HCl, 5-6N in IPA (0.083 mL, 0.415 mmol). The reaction was heated to 50° After 1 h, the reaction was cooled to 23° C., and the product (as HCl salt) was free-based using a Silicycle Si-propylsulfonic acid ion exchange column (catalog # R51230B). The compound was diluted in MeOH and added to a pad of the resin (wetted and flushed with 10 mL MeOH). It was flushed with MeOH (50 mL), and then the product was “released” using 2.0 M NH3 in MeOH solution (50 ml). The final filtrate was concentrated, affording 5-(5-(2,6-difluorophenyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)-N-(piperidin-3-yl)pyridin-3-amine MS (ESI, pos. ion) m/z: 406.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH3:15])=[CH:10][C:11](=O)[NH:12][N:13]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:18])=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([Cl:18])=[CH:10][C:9]=2[CH3:15])=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(=O)[nH]nc1-c1ccc(Br)cc1
Product: Cc1cc(Cl)nnc1-c1ccc(Br)cc1

Procedure:
A 2.0 g. portion of 6-(p-bromophenyl)-5-methyl-3(2H)-pyridazinone and 20 ml. of phosphorus oxychloride are heated on a steam bath for 3 hours. The reaction mixture is poured slowly into crushed ice. The excess phosphorus oxychloride is decomposed. The solid which forms is recovered by filtration, washed with water, dried and recrystallized twice from chloroform, yielding 6-(p-bromophenyl)-5-methyl-3-chloropyridazine, m.p. 197°-200° C.
Reaction SMILES: [CH2:1]([N:4]1[C:8](=[O:9])[C:7]([CH3:11])([CH3:10])[NH:6][C:5]1=[O:12])[C:2]#[CH:3].[I:13]N1C(=O)CCC1=O.CC(C)=O>C(Cl)(Cl)(Cl)Cl.O.[N+]([O-])([O-])=O.[Ag+]>[I:13][C:3]#[C:2][CH2:1][N:4]1[C:8](=[O:9])[C:7]([CH3:10])([CH3:11])[NH:6][C:5]1=[O:12]
Reactant: O=C1CCC(=O)N1I
Reactant: C#CCN1C(=O)NC(C)(C)C1=O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CC1(C)NC(=O)N(CC#CI)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 3-(2-propynyl)-5,5-dimethylhydantoin (1 g, 60 mmole) in CCl4 (20 mL) at room temperature was added N-iodosuccinimide (1.6 g, 7.1 mmole). Dry acetone was added until all materials were dissolved. To the above clear solution was added silver nitrate (0.1 g, 0.58 mmole) and the reaction mixture was stirred at room temperature for 2 hr. The mixture was diluted with water (60 mL) and was extracted with ethyl acetate (3×50 mL). The organic layer was washed with saturated sodium chloride solution (75 mL) and dried with sodium sulfate. After filtering off drying agent and evaporating the solvents, a light yellow solid of 3-(3-iodo-2-propynyl)-5,5-dimethylhydantoin was obtained, 1.6 g (91%), mp=118°-126° C. An NMR spectrum also showed the desired product.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH:8]([N:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1)([CH3:10])[CH3:9]>C(Cl)Cl>[CH:8]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)([CH3:10])[CH3:9]
Reactant: CC(C)N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N1CCNCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.9 %

Procedure:
TFA (15 mL) was slowly added to a stirred solution of tert-butyl 4-isopropylpiperazine-1-carboxylate (13 g crude) in dry DCM (20 mL) under argon atmosphere at 0° C. The resulting reaction mixture was allowed to warm to room temperature and stirred for 18 hr. The reaction mass was concentrated under vacuum and triturated the residue with n-hexane and diethyl ether. Dried under vacuum to afford the title compound (7 g, yield: 97%). MS (ESI): 129.1 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:7][CH:6]=1.[OH-].[Na+].Cl>>[NH2:24][S:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][CH2:12][O:11][C:8]2[CH:9]=[CH:10][C:5]([C:4](=[O:25])[C:3]([OH:26])=[O:2])=[CH:6][CH:7]=2)=[CH:20][CH:19]=1)(=[O:22])=[O:23]
Reactant: COC(=O)C(=O)c1ccc(OCCOc2ccc(S(N)(=O)=O)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NS(=O)(=O)c1ccc(OCCOc2ccc(C(=O)C(=O)O)cc2)cc1
Yield: 93.5 %

Procedure:
A mixture of 4-[[2-[4-(aminosulfonyl)phenoxy]ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester (0.3 g) and 0.5N sodium hydroxide (6 mL) was warmed on the steam bath for 5 minutes and allowed to cool over 10 minutes. The clear solution was acidified with 1N hydrochloric acid (4 mL) and the resulting mixture chilled, filtered, and the solids washed with water. The solids were dried over phosphorus pentoxide at 70° C. and 0.1 mm to give 0.27 g of colorless 4-[[2-[4- (aminosulfonyl)phenoxy]ethyl]oxy]-alpha-oxobenzeneacetic acid as a 4:1 molar hydrate, mp 178°-179° C. with decomposition.
Reaction SMILES: [CH3:1][NH2:2].C([O:5][C:6](=O)[CH2:7][C:8]1[N:9]=[CH:10][C:11]2[CH2:12][N:13]=[C:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[C:15]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:16]=3[C:17]=2[N:18]=1)C>C(O)C>[Cl:23][C:21]1[CH:20]=[CH:19][C:16]2[C:17]3[N:18]=[C:8]([CH2:7][C:6]([NH:2][CH3:1])=[O:5])[N:9]=[CH:10][C:11]=3[CH2:12][N:13]=[C:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[C:15]=2[CH:22]=1
Reactant: CCOC(=O)Cc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Reactant: CN
Solvent: CCO
Product: CNC(=O)Cc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Reaction time: 18 h

Procedure:
Methylamine was bubbled into a solution of 2.6 g (6.34 mmol) of 9-chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepine-2-acetic acid ethylester in 60 ml of ethanol for 10 min. After standing for 18 hr, the reaction was evaporated and the residue was partitioned between 75 ml of dichloromethane and 50 ml of water. The organic layer was dried and evaporated. The residue was crystallized and then recrystallized from dichloromethane/ether to give white rods, mp 175°-177° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:30][CH2:29][C:12]2([C:16](=[O:17])[N:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)[CH2:11][CH2:10]1>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:30][CH2:29][C:12]2([C:16](=[O:17])[N:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:27])([F:28])[F:26])=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O
Solvent: ClCCl
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(c1ccccc1O)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 8-(2-methoxy-phenyl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 7, 16 mg, 0.04 mmol) in DCM (1 mL) at −78° C. was added borontribromide (1M, 110 uL, 0.12 mmol) drop wise. The reaction mixture was warmed to r.t. and stirring was continued overnight. The reaction mixture was quenched with sat. NaHCO3 and extracted with DCM. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated under reduced pressure to yield the title compound a white solid (9 mg, 61%). MS (ESI): 407.4 (MH+).