Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([C:18]2[N:22]3[N:23]=[C:24](Cl)[CH:25]=[C:26]([NH:27][CH:28]4[CH2:30][CH2:29]4)[C:21]3=[N:20][CH:19]=2)=[O:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([NH2:39])[CH2:35][CH2:34]1>CO>[NH2:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([NH:39][C:24]2[CH:25]=[C:26]([NH:27][CH:28]3[CH2:30][CH2:29]3)[C:21]3[N:22]([C:18]([C:16]([NH:15][C:11]4[CH:10]=[C:9]([O:8][CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[N:14]=[CH:13][N:12]=4)=[O:17])=[CH:19][N:20]=3)[N:23]=2)[CH2:35][CH2:34]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: O=C(Nc1cc(OCc2ccccc2)ncn1)c1cnc2c(NC3CC3)cc(Cl)nn12
Solvent: CO
Product: N[C@H]1CC[C@H](Nc2cc(NC3CC3)c3ncc(C(=O)Nc4cc(OCc5ccccc5)ncn4)n3n2)CC1

Procedure:
N-(6-(benzyloxy)pyrimidin-4-yl)-6-chloro-8-(cyclopropylamino)imidazo[1,2-b]pyridazine-3-carboxamide (70 mg, 0.161 mmol) and trans-1,4-diaminocyclohexane (367 mg, 3.21 mmol) were heated at 160° C. for 2 hrs. The reaction mixture was diluted with methanol and purified by preparative HPLC (Phenomenex Axia Luna 5 micron 30×100 mm) 10% B (Solvent B=90% MeOH-10% H2O-0.1% TFA) to 100% B in A (Solvent A=10% MeOH-90% H2O-0.1% TFA)) to isolate 6-((trans)-4-aminocyclohexylamino)-N-(6-(benzyloxy)pyrimidin-4-yl)-8-(cyclopropylamino)imidazo[1,2-b]pyridazine-3-carboxamide (37 mg, 0.072 mmol, 44.9% yield) as light yellow solid. LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA) Rt=1.818 (M+H=514.25).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:20].[F:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30](O)=[O:31])[CH:25]=[C:26]([F:28])[CH:27]=1>>[F:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30]([NH:1][N:2]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:20])=[O:31])[CH:25]=[C:26]([F:28])[CH:27]=1
Reactant: Cc1ccc(-c2nn(N)c(=O)c3ccccc23)cc1C
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Product: Cc1ccc(-c2nn(NC(=O)Cc3cc(F)cc(F)c3)c(=O)c3ccccc23)cc1C

Procedure:
The product of Example 163A and 2-(3,5-difluorophenyl)acetic acid were treated using a method similar to that described in Example 17C to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.74 (s, 1H), 8.39-8.42 (m, 1H), 7.89-8.02 (m, 2H), 7.74-7.77 (m, 1H), 7.25-7.39 (m, 3H), 7.12-7.18 (m, 3H), 3.77 (s, 2H), 2.32 (s, 3H), 2.31 (s, 3H); MS (APCI+) M/Z 420 (M+H)+.
Reaction SMILES: F[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH:15]=[CH2:16])[CH:3]=1.[C:17]([NH2:21])([CH3:20])([CH3:19])[CH3:18]>N1C=CC=CC=1>[C:17]([NH:21][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH:15]=[CH2:16])[CH:3]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)N
Reactant: C=Cc1cc(F)c([N+](=O)[O-])cc1C(=O)OC
Solvent: c1ccncc1
Product: C=Cc1cc(NC(C)(C)C)c([N+](=O)[O-])cc1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 10.45 g of methyl 4-fluoro-5-nitro-2-vinylbenzoate and 104.5 mL of pyridine was added 14.69 mL of tert-butylamine, followed by stirring at room temperature overnight. The solvent was evaporated under reduced pressure, and to the residue were added water and ethyl acetate, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 14 g of methyl 4-(tert-butylamino)-5-nitro-2-vinylbenzoate as a brown oil.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)=[CH:9][C:7]=1[NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH:22](=O)[CH3:23].OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:14]1[C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=[C:13]1[C:10]1[CH:11]=[CH:12][C:6]2[N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:22]([CH3:23])=[N:8][C:7]=2[CH:9]=1
Reactant: CC(C)(C)Nc1ccc(-c2nc3ccccc3o2)cc1N
Reactant: CC=O
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc2cc(-c3nc4ccccc4o3)ccc2n1C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.2 %

Procedure:
To a solution of 2-(2-tert-butylaminoanilin-5-yl)benzoxazole (see Working Example 29-1) (45.0 mg, 0.160 mmol) in dimethylformamide (2 mL) was added an aqueous solution of acetaldehyde (approx. 90%, 235 μL, 0.480 mmol) and oxone (63.9 mg, 0.104 mmol), and this was stirred at room temperature for 3 hours. After the reaction was complete, aqueous potassium carbonate solution was added, this was filtered and washed with water. The crystals obtained were purified by silica gel column chromatography to yield the title compound (18.2 mg, 38% yield) as white crystals.
Reaction SMILES: [O:1]=[S:2]([Cl:4])Cl.N([O-])=[O:6].[Na+].N[C:10]1[CH:11]=[CH:12][C:13]([C:16]#[N:17])=[N:14][CH:15]=1>O.Cl>[C:16]([C:13]1[N:14]=[CH:15][C:10]([S:2]([Cl:4])(=[O:1])=[O:6])=[CH:11][CH:12]=1)#[N:17]
Reactant: N#Cc1ccc(N)cn1
Reactant: O=N[O-]
Reactant: O=S(Cl)Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc(S(=O)(=O)Cl)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68 %

Procedure:
SOCl2 (1.8 ml, 24.8 mmol) was added dropwise to ice water and stirred for 18 h at room temperature. CuCl2 (22 mg, 0.22 mmol) was added at 0° C. and the mixture was stirred for 15 min. In a separate flask, a solution of NaNO2 (450 mg, 6.52 mmol) in water (4.5 ml) was added to a stirred solution of 5-amino-pyridine-2-carbonitrile (534 mg, 4.5 mmol) in conc. HCl (4.5 ml) at 0° C., over 15 min. The diazonium salt solution was added dropwise to the thionyl chloride/CuCl2 solution at 0° C. and stirring was continued for 1 h. The reaction mixture was extracted with DCM and the combined organic phases were dried (Na2SO4) and concentrated in vacuo to give the title compound (620 mg) which was used in the next step without purification. The structure was confirmed by 1H NMR.
Reaction SMILES: [CH:1]([NH:4][C@@H:5]([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])([CH3:3])[CH3:2].Cl[C:13]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][N:14]=1>CCOC(C)=O>[CH2:9]([O:8][C:6](=[O:7])[C@@H:5]([N:4]([CH:1]([CH3:3])[CH3:2])[C:13]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][N:14]=1)[CH3:11])[CH3:10]
Reactant: COC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: CCOC(=O)[C@H](C)NC(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](C)N(c1ncc(C(=O)OC)cc1[N+](=O)[O-])C(C)C
Temperature: 90 °C
Reaction time: 20 h
Yield: 41.6 %

Procedure:
(S)-ethyl 2-(isopropylamino)propanoate (2.83 g, 17.8 mmol) was added to methyl 6-chloro-5-nitronicotinate (1.72 g, 7.94 mmol) and the reaction mixture was stirred in a closed vial at 90° C. for 20 h. It was cooled and diluted with EtOAc (25 mL). The resulting precipitate was filtered off, the filtrate was concentrated in vacuo and purified using flash column chromatography on silica gel (220 g SiO2, hexanes:ethyl acetate 4:1) to afford the title compound as yellow oil (1.12 g, 42%). 1H NMR (400 MHz, CHLOROFORM-d) δ (ppm): 1.18 (t, J=7.07 Hz, 3H) 1.30 (d, J=6.32 Hz, 3H) 1.36 (d, J=6.57 Hz, 3H) 1.66 (d, J=6.82 Hz, 3H) 3.48-3.62 (m, 1H) 3.90 (s, 3H) 4.03 (q, J=6.65 Hz, 1H) 4.06-4.21 (m, 2H) 8.54 (d, J=2.02 Hz, 1H) 8.70 (d, J=2.02 Hz, 1H); [M+H] calc'd for C15H21N3O6, 340. found, 340.
Reaction SMILES: [ClH:1].[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:31]CC(OC)=O)[C:9]([C:11]1[CH:16]=[CH:15][N:14]2[C:17]([CH3:30])=[C:18]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=3)[N:19]=[C:13]2[CH:12]=1)=[O:10].Cl.C(=O)([O-])[O-].[NH4+:42].[NH4+].[C:44]([O:47][CH2:48][CH3:49])(=[O:46])[CH3:45].C(O)C.N>C(O)C>[ClH:1].[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:31][CH2:45][C:44]([O:47][CH2:48][CH3:49])=[O:46])[C:9]([C:11]1[CH:16]=[CH:15][N:14]2[C:17]([CH3:30])=[C:18]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](=[NH:42])[NH2:29])=[CH:24][CH:23]=3)[N:19]=[C:13]2[CH:12]=1)=[O:10]
Reactant: COC(=O)CCN(C(=O)c1ccn2c(C)c(CCc3ccc(C#N)cc3)nc2c1)c1ccccn1
Reactant: CCOC(C)=O
Reactant: [NH4+]
Agent: Cl
Agent: N
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccn2c(C)c(CCc3ccc(C(=N)N)cc3)nc2c1)c1ccccn1
Yield: 53 %

Procedure:
Prepared analogously to Example 1 from 3-methyl-2-[2-(4-cyanophenyl)ethyl]-imidazo[1.2-a]pyridin-7-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide-hydrochloride and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 53% of theory, C28H30N6O3 (498.59) Rf value: 0.42 (silica gel; ethyl acetate/ethanol/ammonia =50:45:5) ##EQU136##
Reaction SMILES: [F:1][C:2]1([F:22])[CH:6](OS(C(F)(F)F)(=O)=O)[CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.[N-:23]=[N+:24]=[N-:25].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C=O)C.CC(OC)(C)C>[N:23]([CH:6]1[CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3][C:2]1([F:22])[F:1])=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CC(OS(=O)(=O)C(F)(F)F)C(F)(F)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)N1CC(N=[N+]=[N-])C(F)(F)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
tert-Butyl 3,3-difluoro-4-{[(trifluoromethyl)sulfonyl]oxy}pyrrolidine-1-carboxylate (5.56 g, 15.2 mmol) was dissolved in DMF (20 mL) and cooled in an ice bath under nitrogen atmosphere. Tetrabutylammonium azide (TBA-N3, 4.8 g, 17 mmol, 1.1 mol eq) in DMF (15 mL) was added slowly over 15 min via an addition funnel. The reaction mixture was stirred in the cold bath and was allowed to warm to ambient temperature gradually. After 16 hr, the reaction was diluted with MTBE (300 mL), washed with sat. aq. NaHCO3 (2×30 mL), and brine (2×30 mL), dried over Na2SO4 and evaporated to give a residue. This crude material was purified on silica (40 g) with gradients from 100% heptane to 20% ethyl acetate-80% heptane to give the title product as a colorless oil (3.02 g, 80% yield, >95% purity). 1H NMR (400 MHz, chloroform-d) δ ppm 4.06 (dtd, J=8.86, 5.41, 5.41, 3.91 Hz, 1 H) 3.65-3.83 (m, 3 H) 3.36-3.57 (m, 1 H) 1.47 (s, 9 H). 19F NMR (376 MHz, chloroform-d) δ ppm −106.10-−102.44 (m, 1 F) −120.14-−116.68 (m, 1 F). m/z (ESI+) for C9H14F2N4O2 149 (small)/123 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3](Br)=[O:4].[NH2:6][CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8]1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:39]=[CH:40][C:41]=1[O:42][CH3:43])[CH2:21][CH:22]1[C:28]2[CH:29]=[C:30]([O:35][CH3:36])[C:31]([O:33][CH3:34])=[CH:32][C:27]=2[S:26](=[O:38])(=[O:37])[CH2:25][CH2:24][NH:23]1>>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:39]=[CH:40][C:41]=1[O:42][CH3:43])[CH2:21][CH:22]1[C:28]2[CH:29]=[C:30]([O:35][CH3:36])[C:31]([O:33][CH3:34])=[CH:32][C:27]=2[S:26](=[O:38])(=[O:37])[CH2:25][CH2:24][N:23]1[CH2:2][C:3]([NH:6][CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8]1)=[O:4]
Reactant: COc1ccc(CC2NCCS(=O)(=O)c3cc(OC)c(OC)cc32)cc1OC
Reactant: O=C(Br)CBr
Reactant: NC1CCc2ccccc21
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3S(=O)(=O)CCN2CC(=O)NC2CCc3ccccc32)cc1OC

Procedure:
prepared by reaction of 2-bromoacetyl bromide with rac-1-aminoindane and 9-(3,4-dimethoxy-benzyl)-2,3-dimethoxy-6,7,8,9-tetrahydro-5-thia-8-aza-benzocycloheptene-5,5-dioxide
Reaction SMILES: [Si]([O:8][CH:9]([CH2:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)/[CH:10]=[CH:11]/[CH:12]1[CH2:19][CH2:18][CH:17]2[CH:13]1[CH2:14]/[C:15](=[CH:21]\[CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])/[C:16]2=[O:20])(C(C)(C)C)(C)C.O.C(O)(=O)C.O1CCCC1>[Cl-].[Na+]>[OH:8][CH:9]([CH2:29][O:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)/[CH:10]=[CH:11]/[CH:12]1[CH2:19][CH2:18][CH:17]2[CH:13]1[CH2:14]/[C:15](=[CH:21]\[CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])/[C:16]2=[O:20]
Reactant: COC(=O)CCC/C=C1\CC2C(/C=C/C(COc3ccccc3)O[Si](C)(C)C(C)(C)C)CCC2C1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)CCC/C=C1\CC2C(/C=C/C(O)COc3ccccc3)CCC2C1=O
Yield: 98 %

Procedure:
6-[(E)-3-tert-Butyldimethylsilyloxy-4-phenoxybut-1-enyl]-3-[(E)-4-methoxycarbonylbutylidene]bicyclo[3,3,0]octan-2-one (13 mg), prepared as described in Reference Example 51 and in the form of (±)-6β-[(E)-3α-tert-butyldimethylsilyloxy-4-phenoxybut-1-enyl]-3-[(E)-4-methoxycarbonylbutylidene]bicyclo[3,3,0]octan-2-one, otherwise known as (±)-methyl (5E,13E)-(9S,15R)-6a-oxo-6,9-methano-15-tert-butyldimethylsilyloxy-16-phenoxy-17,18,19,20-tetranorprosta-5,13-dienoate, and a solution of water, glacial acetic acid and tetrahydrofuran (0.53 ml; 7:13:2 by volume) were stirred together at 40° C. for 4 hours. After cooling, the mixture was diluted with saturated aqueous sodium chloride solution and extracted with diethyl ether. The extract was washed with aqueous sodium bicarbonate solution (1M) and then with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The residue was subjected to medium pressure liquid chromatography on silica gel, eluting with a mixture of ethyl acetate and hexane (9:13 v/v), to give 6-[(E)-3-hydroxy-4-phenoxybut-1-enyl]-3-[(E)-4-methoxycarbonylbutylidene]bicyclo[3,3,0]octan-2-one (9.9 mg), in the form of (±)-6β-[(E)-3α-hydroxy-4-phenoxybut-1-enyl]-3-[(E)-4-methoxycarbonylbutylidene]bicyclo[3,3,0]octan-2-one, otherwise known as (±)-methyl (5E,13E)-(9S,15R)-6a-oxo-6,9-methano-15-hydroxy-16-phenoxy-17,18,19,20-tetranorprosta-5,13-dienoate [NMR (in deuterochloroform): multiplets at 6.8-7.3, 6.4-6.6, 5.6-5.8, 4.3-4.6, 3.8-4.0, 1.3- 2.8 p.p.m., singlet at 3.6 p.p.m⟧
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([P:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[S:23]([C:28]1[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=1)([O:26][CH3:27])(=[O:25])=[O:24]>>[S:23]([C:28]1[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=1)([O-:26])(=[O:25])=[O:24].[CH3:27][P+:8]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: Clc1ccc(P(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Product: C[P+](c1ccc(Cl)cc1)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Yield: 91.7 %

Procedure:
A mixture of 2.08 g (5.69 mmol) of tris (4-chlorophenyl)phosphine and 1.03 g (5.53 mmol) of methyl tosylate was allowed to react for 1 hr at 125° C. A total of 2.80 g (5.07 mmol, 91.7%) of product was obtained, which was further purified by recrystallization from 97:3 toluene-ethanol.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH2:15])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1.[O:16]1[C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=[N:17]1>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:21]([C:20]4[O:16][N:17]=[CH:18][CH:19]=4)=[O:22])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1
Reactant: O=C(Cl)c1ccno1
Reactant: Nc1nc2cccc(-c3ccoc3)n2n1
Product: O=C(Nc1nc2cccc(-c3ccoc3)n2n1)c1ccno1

Procedure:
The title compound was prepared following procedure described for example 19, but starting from 5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 50 mg; 0.25 mmol; 1.0 eq.) and isoxazole-5-carbonyl chloride (49 mg; 0.37 mmol; 1.5 eq.) as a white powder (19.4 mg, 26%). HPLC, Rt: 2.62 min. (purity 95.3%). LC/MS, M+(ESI): 296.4, M−(ESI): 294.3.
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7].C([O-])([O-])=O.[Na+].[Na+].[CH3:32][O:33][C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O)=[O:35]>COCCOC>[CH3:32][O:33][C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])=[O:35]
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccc(F)cc1Br
Reactant: COC(=O)c1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1ccccc1-c1cc(F)ccc1OCC(=O)N(NC(=O)c1ccccc1)C(C)C
Yield: 14.1 %

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N′-isopropyl-hydrazide (50 mg, 0.122 mmol) in DME (3 ml)/2M Na2CO3 (0.215 ml, 0.427 mmol) was treated with 2-methoxycarbonylphenyl boronic acid (33 mg, 0.183 mmol) and Pd[PPh3]4 (27 mg, 0.0244 mmol) for 12 hours at 90° C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was purified first on a silica gel column with a 20-30% ethyl acetate/hexanes gradient and then by RP HPLC to afford the product as a white solid (8 mg, 14%). MS m/e 465.23 (M+H+)
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1.[S:13](Cl)([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14]>C1COCC1>[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][N:10]2[S:13]([C:16]2[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[CH:6][CH:5]=1
Reactant: Clc1ccc2cc[nH]c2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ccc3ccc(Cl)cc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Intermediate 147.3 is prepared in analogy to a published literature procedure (J. Med. Chem. 2006, 49, 3101-3115). 55% of NaH in mineral oil (881 mg, 20.2 mmol) is added to a solution of 6-Chloroindole (3.0 g, 19.8 mmol) in THF (28 mL) at 0° C. After 1 h, TsCl (3.85 g, 20.2 mmol) is added, and the reaction mixture is stirred at RT. After completion, the reaction mixture is quenched by saturated aqueous NaHCO3 and diluted with Et2O. The organic layer is dried over Na2SO4 and evaporated in vacuo to provide crude solid. The crude product is washed with small amount of Et2O to give the title compound as orange crystal; ES-MS: M+=306.1: AtRet=5.60.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4]Br.[C-:12]#[N:13].[Na+].O.CCOC(C)=O>CS(C)=O>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4][C:12]#[N:13]
Reactant: [C-]#N
Reactant: COc1ccc(Br)c(CBr)c1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(Br)c(CC#N)c1
Temperature: 90 °C

Procedure:
2-Bromo-5-methoxybenzyl bromide (2 g, 7.1 mmol) and sodium cyanide (0.526 g, 10.7 mmol) were combined in DMSO (20 mL) and heated to 90° C. for 3 hours. Once no starting material was seen by analytical tlc, the mixture was worked-up with H2O and EtOAc to give the desired product as a colorless oil.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1>O1CCCC1>[Br:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:14])=[CH:11][CH:10]=1
Reactant: NC1CCCCC1
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)c1ccc(Br)cc1
Reaction time: 0.33 h
Yield: 80.8 %

Procedure:
Cyclohexylamine (9.111 g) was dissolved in tetrahydrofuran (100 ml), followed by the addition of 4-bromobenzoyl chloride (5.04 g)/tetrahydrofuran solution (30 ml) under ice-cooling, and the mixture was stirred for 20 min. The reaction mixture was partitioned between ethyl acetate and water. The resulting organic layer was washed with water, dried (over MgSO4) and evaporated. The resulting residue was recrystallized from ethyl acetate/hexane, to give the title compound as a pale pink solid (5.236 g, yield; 83%).
Reaction SMILES: [CH3:1][O:2][C:3]1([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[CH2:6][O:5][CH2:4]1.Cl.[NH2:16][OH:17].C(N(CC)CC)C>C(O)C>[OH:17][N:16]=[C:11]([C:10]1[CH:9]=[CH:8][C:7]([C:3]2([O:2][CH3:1])[CH2:6][O:5][CH2:4]2)=[CH:14][CH:13]=1)[NH2:12]
Reactant: NO
Reactant: COC1(c2ccc(C#N)cc2)COC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COC1(c2ccc(C(N)=NO)cc2)COC1
Temperature: 25 °C
Yield: 88.6 %

Procedure:
A solution of 4-(3-methoxyoxetan-3-yl)benzonitrile (Step 1, 500 mg, 2.64 mmol), hydroxylamine hydrochloride (403 mg, 5.81 mmol) and triethylamine (810 μL, 5.81 mmol) in ethanol (12.5 mL) was stirred and heated at reflux for 2 h. After being cooled to rt, the reaction mixture was evaporated to dryness. The resulting material was treated with a mixture of water (5 mL) and diethyl ether (0.5 mL). The solid was isolated by filtration, washed with a small amount of cold water and dried in a vacuum oven to afford the title compound as a colorless solid (520 mg, 86%): 1H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 7.73 (d, 2H), 7.43 (d, 2H), 5.84 (broad s, 2H), 4.79-4.75 (m, 4H), 3.01 (s, 3H); DCI(NH3)-MS m/z 223 (MH)+; HPLC RT (Method I) 2.54 min.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[C:11]([NH:16][C:17](=[O:27])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N:24]([CH3:26])[CH3:25])[CH:19]=2)[CH:12]=[CH:13][C:14]=1[CH3:15].[Cl:28][CH2:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](Cl)=[O:34]>C(Cl)Cl>[CH3:25][N:24]([CH3:26])[C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[C:17]([NH:16][C:11]1[CH:12]=[CH:13][C:14]([CH3:15])=[C:9]([NH:8][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][CH:38]=[C:30]([CH2:29][Cl:28])[CH:31]=2)[CH:10]=1)=[O:27]
Reactant: O=C(Cl)c1cccc(CCl)c1
Reactant: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 102.1 %

Procedure:
Triethylamine (1.55 ml) was added to a stirred mixture of N-(3-amino-4-methylphenyl)-3-dimethylaminobenzamide (3.0 g), 3-chloromethylbenzoyl chloride (2.76 g) and methylene chloride (50 ml) and the reaction mixture was stirred at ambient temperature for 16 hours. The mixture was evaporated and the residue was triturated under water. The solid so obtained was isolated, washed in turn with a saturated aqueous sodium bicarbonate solution, water and isohexane and dried under vacuum at 55° C. There was thus obtained the title compound (4.8 g); NMR Spectrum: (DMSOd6) 2.19 (s, 3H), 2.96 (s, 6H), 4.84 (s, 2H), 6.9 (d, 1H), 7.26 (m, 3H), 7.5-7.7 (m, 3H), 7.8-8.1 (m, 4H), 9.97 (s, 1H), 10.09 (s, 1H); Mass Spectrum: M−H−420.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][N:10]1[C:19]2[C:14](=[C:15]([N+:20]([O-])=O)[CH:16]=[CH:17][CH:18]=2)[C:13](=[O:23])[C:12]([CH3:24])=[CH:11]1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[ClH:25].[H][H]>CO.CCOCC.[Pd]>[ClH:25].[NH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:14]=1[C:13](=[O:23])[C:12]([CH3:24])=[CH:11][N:10]2[CH2:9][P:4](=[O:8])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2]
Reactant: CCOP(=O)(Cn1cc(C)c(=O)c2c([N+](=O)[O-])cccc21)OCC
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CCOP(=O)(Cn1cc(C)c(=O)c2c(N)cccc21)OCC
Yield: 99 %

Procedure:
A solution of (3-Methyl-5-nitro-4-oxo-4H-quinolin-1-ylmethyl)-phosphonic acid diethyl ester (Compound 303B, 20 mg; 0.05 mmol) in methanol (5 mL) was charged with Pd/C (5 mg) and 1M HCl in ether (1 mL) under nitrogen and stirred under 1 atmosphere of hydrogen overnight at RT. The solution was filtered the filtrate concentrated to get the final compound (yield 20 mg; 99%; tlc 1:9 MeOH:DCM); 1H NMR (300 MHz, CDCl3), δ ppm, 8.12 (s, 1H), 8.01 (d, 6Hz, 1H,) 7.88-7.83 (m, 1H) 7.40 (d, J=9Hz, 1H) 4.12-4.13 (m, 4H,) 3.31-3.29 (m, 2H), 2.14 (s, 3H), 1.27-1.25 (m, 6H)