Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=C(F)C=CC=1CN1C2C=CC=C(N)C=2C=N1.[N:20]1[CH:21]=[C:22]([C:29]([OH:31])=O)[N:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=12.[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38][N:39]1[C:47]2[CH:46]=[CH:45][CH:44]=[C:43]([NH2:48])[C:42]=2[CH:41]=[N:40]1>>[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38][N:39]1[C:47]2[C:42](=[C:43]([NH:48][C:29]([C:22]3[N:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]4=[N:20][CH:21]=3)=[O:31])[CH:44]=[CH:45][CH:46]=2)[CH:41]=[N:40]1
Reactant: O=C(O)c1cnc2ccccn12
Reactant: Nc1cccc2c1cnn2Cc1ccccn1
Agent: Nc1cccc2c1cnn2Cc1ccc(F)cc1F
Product: O=C(Nc1cccc2c1cnn2Cc1ccccn1)c1cnc2ccccn12

Procedure:
Prepared according to the method of Example 109, replacing 7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid and 1-(2,4-difluorobenzyl)-1H-indazol-4-amine with imidazo[1,2-a]pyridine-3-carboxylic acid and 1-(pyridin-2-ylmethyl)-1H-indazol-4-amine, respectively. MS (APCI) m/z=369 (M+H).
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([CH2:12]OS(C3C=CC(C)=CC=3)(=O)=O)[O:7][C:6]=2[CH:5]=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[CH3:28][NH:29][CH2:30][CH2:31][CH3:32]>C(#N)C>[F:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([CH2:12][N:29]([CH3:28])[CH2:30][CH2:31][CH3:32])[O:7][C:6]=2[CH:5]=[C:4]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:3]=1
Reactant: CCCNC
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3c(F)cc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CCCN(C)CC1COc2c(F)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 42 using [5-fluoro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl-4-methylbenzenesulfonate (0.005 g, 0.012 mmol), N-methyl-propan-1-amine (0.5 ml), ACN (2.5 ml). MS m/z (rel. intensity, 70 eV) 317 (M+, 0.5), 288 (8), 86 (bp), 84 (6), 58 (8).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH3:22])[N:17]=[CH:16]3)(=[O:10])=[O:9])=[C:4]([CH2:23][CH3:24])[CH:3]=1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.CN(C=O)C.C[CH2:67][O:68][C:69](C)=[O:70].CCCCCC>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CO>[CH2:23]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[S:8](=[O:10])(=[O:9])[NH:11][CH2:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([CH3:22])[N:17]=[CH:16]2)[C:69]([O:68][CH3:67])=[O:70])[CH3:24]
Reactant: CCc1cc(Br)ccc1S(=O)(=O)NCc1ccc2c(cnn2C)c1
Reactant: CCOC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1cc(C(=O)OC)ccc1S(=O)(=O)NCc1ccc2c(cnn2C)c1
Temperature: 100 °C
Reaction time: 24 h
Yield: 64 %

Procedure:
A mixture of 4-bromo-2-ethyl-N-((1-methyl-1H-indazol-5-yl)methyl)benzenesulfonamide (prepared in step-1 of Example 4, 263 mg, 0.64 mmol), palladium(II) acetate (43 mg, 0.19 mmol), 1,3-bis(diphenylphosphino)propane (80 mg, 0.19 mmol) and triethylamine (130 mg, 1.29 mmol) in the mixture of DMF (7 mL)-MeOH (2.8 mL) was stirred at 100° C. for 1 day under carbon monooxide atmosphere. Then, to the mixture was added palladium(II) acetate (43 mg, 0.19 mmol), 1,3-bis(diphenylphosphino)propane (80 mg, 0.19 mmol). The mixture was stirred at 100° C. for 2 hrs under carbon monooxide atmosphere. The mixture was poured into EtOAc-hexane (2:1) and washed with 2 M aqueous HCl and H2O. The organic layer was dried over Na2SO4, filtered and concentrated. The residual solid was purified by silicagel column chromatography (0-40% EtOAc in hexane) to give titled compound (160 mg, 64%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:5][C@H:6]([CH3:12])[C:7]=1[C:8]([O:10][CH3:11])=[O:9])=[O:4].[CH3:13][S:14](Cl)(=[O:16])=[O:15].C(N(CC)CC)C.[Cl-].[Na+]>C1(C)C=CC=CC=1.O>[S:14]([O:1][C:2]1[C:3]([O:5][C@H:6]([CH3:12])[C:7]=1[C:8]([O:10][CH3:11])=[O:9])=[O:4])([CH3:13])(=[O:16])=[O:15]
Reactant: COC(=O)C1=C(O)C(=O)O[C@@H]1C
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)C1=C(OS(C)(=O)=O)C(=O)O[C@@H]1C

Procedure:
137.76 g of (R)-2-hydroxy-3-methoxycarbonyl-2-penten-4-olide are dissolved in 660 ml of toluene and at -10° C. 110 g of methanesulphonyl chloride and then, within a period of 1 hour, 97 g of triethylamine, are added. 350 ml of water and 150 ml of saturated sodium chloride solution are added, the toluene product phase is removed and the aqueous phase is re-extracted twice with 250 ml of toluene. The toluene phases are washed with sodium chloride solution and with water and concentrated by evaporation. Orange-red oil, [α]D20 =+10.6° (3% in CHCl3).
Reaction SMILES: C(OC([N:6]=[S:7]([CH3:35])([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]2[CH:26]=[C:25]3[C:20]([C:21]([NH:27][C:28]4[S:29][CH:30]=[N:31][N:32]=4)=[N:22][CH:23]=[N:24]3)=[CH:19][C:18]=2[O:33][CH3:34])[CH:10]=1)=[O:8])=O)C.[O-]CC.[Na+].CCCCCC.ClCCl.CO>CO>[CH3:34][O:33][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:17]=1[O:16][CH2:15][C:11]1[CH:10]=[C:9]([S:7]([CH3:35])(=[NH:6])=[O:8])[CH:14]=[CH:13][CH:12]=1)[N:24]=[CH:23][N:22]=[C:21]2[NH:27][C:28]1[S:29][CH:30]=[N:31][N:32]=1
Reactant: CCOC(=O)N=S(C)(=O)c1cccc(COc2cc3ncnc(Nc4nncs4)c3cc2OC)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CCCCCC
Product: COc1cc2c(Nc3nncs3)ncnc2cc1OCc1cccc(S(C)(=N)=O)c1
Yield: 35 %

Procedure:
According to GWP 6, the reaction of (RS)-N-(ethoxycarbonyl)-S-methyl-S-[3-({[6-methoxy-4-(1,3,4-thiadiazol-2-ylamino)quinazolin-7-yl]oxy}methyl)phenyl]-sulphoximide (37 mg, 0.072 mmol) with sodium ethoxide (25 mg, 0.39 mmol) and chromatographic purification (silica gel, hexane, dichloromethane/methanol: 0→15% methanol) gives the desired product in 35% yield (11 mg).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:15]([CH3:22])([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CC#N.C(Cl)(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])([CH3:22])[CH3:21])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: CCOC(=O)C(C)(C)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Yield: 98.5 %

Procedure:
Amine preparation: a mixture of BOC-piperazine (1.87 g), ethyl 2-bromoisobutyrate (5.90 g) and potassium carbonate (1.53 g) in MeCN (20 mL) was heated in a sealed tube at 80° C. for 3 days. The reaction mixture was cooled, diluted with chloroform, washed with brine, dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash column chromatography to yield 4-(1-ethoxycarbonyl-1-methyl-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (2.97 g).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10](=[O:13])[N:9]([C:14]3[CH:15]=[C:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:17]=[CH:18][CH:19]=3)[C:7]=2[N:8]=1.C(OO)(=[O:30])C.S([O-])([O-])(=O)=S.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][S:2]([C:3]1[N:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10](=[O:13])[N:9]([C:14]3[CH:15]=[C:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])[CH:17]=[CH:18][CH:19]=3)[C:7]=2[N:8]=1)=[O:30]
Reactant: CSc1ncc2ccc(=O)n(-c3cccc(NC(=O)OC(C)(C)C)c3)c2n1
Reactant: CC(=O)OO
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1ncc2ccc(=O)n(-c3cccc(NC(=O)OC(C)(C)C)c3)c2n1
Temperature: 0 °C
Reaction time: 0.12 h
Yield: 104.4 %

Procedure:
At 0° C., a suspension of tert-butyl (3-(2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (51) (3.57 g, 9.29 mmol) in DCM (80 mL) was treated with peracetic acid (32 wt % in AcOH, 1.95 mL, 9.29 mmol) slowly dropwise. After 5-10 min, the reaction mixture became a homogeneous yellow solution, and after 20 min, it became a suspension again. After 1 h, the reaction mixture was treated with DCM (50 mL) followed by a solution of aqueous sodium thiosulfate and stirred at 0° C. for 5 min. It was then treated with a saturated solution of NaHCO3, extracted with DCM (6×50 mL), dried over MgSO4, filtered and concentrated affording tert-butyl (3-(2-(methylsulfinyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (52) (2.50 g, 9.70 mmol, 67% yield) as a light yellow crystalline solid. The crude material was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.58 (1H, s), 9.28 (1H, s), 8.18 (1H, d, J=9.6 Hz), 7.53 (1H, s), 7.37-7.47 (2H, m), 6.89-6.95 (2H, m), 2.71 (3H, s), 1.46 (9H, s). m/z (ESI, +ve ion) 422.9 (M+Na)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][NH:12][C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19]CC)=[O:18])=[CH:15][CH:14]=1.[OH-].[K+].C(O)C.O.Cl>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][NH:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:22][CH:23]=1
Reactant: CCOC(=O)c1ccc(NCCCc2ccccc2OC)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccccc1CCCNc1ccc(C(=O)O)cc1

Procedure:
A mixture of 7.0 g. of ethyl p-[3-(o-methoxyphenyl)propyl]aminobenzoate (prepared as described in Example 41), 7.0 g. of potassium hydroxide and 100 ml. of ethanol-water (9:1) is refluxed for 3.5 hours, acidified while hot with concentrated hydrochloric acid, diluted with water and chilled. The mixture is filtered and the solid washed with water to give off-white crystals, m.p. 155°-157° C. Recrystallization from ethanol gives off-white crystals, m.p. 156°-158° C.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([NH2:23])[C:5]2[N:6]=[C:7]([NH:20][CH2:21][CH3:22])[N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[CH2:24]=[CH:25][CH2:26][CH2:27][CH2:28][CH3:29].CO.CC#N>C(Cl)Cl.O>[CH:24](/[C:2]1[N:3]=[C:4]([NH2:23])[C:5]2[N:6]=[C:7]([NH:20][CH2:21][CH3:22])[N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11])=[CH:25]\[CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: C=CCCCC
Reactant: CCNc1nc2c(N)nc(I)nc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: CCCC/C=C/c1nc(N)c2nc(NCC)n([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1

Procedure:
The reaction was performed with 2-iodo-8-ethylaminoadenosine (8, 740 mg, 1.70 mmol) and (E)-1-borocatechol)-1-hexene (5.09 mmol). The mixture was purfied by column chromatography (10–20% MeOH in CH2Cl2).Yield 23 mg (0.06 mmol, 5%), mp 128–130÷C; Rƒ 0.61 (20% MeOH in CH2Cl2); 1H NMR (MeOD-d4) δ 6.92–6.82 (m, 1H, ═CHCH2), 6.29 (d, 1H, J=14.04 Hz, ═CH), 6.02 (d, 1H, J =7.64 Hz<H-1′), 4.80–4.76 (m, 1H, H-2′), 4.29–4.27 (m, 1H, H-3′), 4.13–4.11 (m, 1H, H4′), 3.81 (q, 2H, J=10.89 Hz, H-5′), 3.42 (q, 2H, J=6.02 Hz, NHCH2), 2.24 (q, 2H, J=6.00 Hz, ═CHCH2), 1.53–1.33 (m, 4H, CH2CH2), 1.28 (t, 3H, J=7.72 Hz, NHCH2CH3), 0.94 (t, 3H, J=7.11 Hz, CH3); MS m/z 393 (M+H)+; HPLC, System A: 20–100% CH3CN in H2O in 35 min., retention time=7.42 min.; System B: 30–100% CH3OH in H2O in 40 min., retention time=20.16 min.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[S:21]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22]1>>[CH3:20][C:18]1[NH:17][N:16]=[C:15]([NH:14][C:4]2[N:3]=[C:2]([C:23]3[CH:24]=[CH:25][S:21][CH:22]=3)[C:11]3[C:6]([CH:5]=2)=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=3)[CH:19]=1
Reactant: COc1cccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc12
Reactant: OB(O)c1ccsc1
Product: COc1cccc2c(-c3ccsc3)nc(Nc3cc(C)[nH]n3)cc12

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-5-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and thiophene-3-boronic acid to give (5-methyl-1H-pyrazol-3-yl)-(1-thiophen-3-yl-5-methoxy-isoquinolin-3-yl)-amine. LC-MS m/e 337(MH+).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])=[CH:6][N:5]=[C:4]([CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[N:3]=1.[CH3:22][N:23]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[C:25]([CH3:38])[C:24]1=[O:39]>>[F:16][C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[O:8][C:7]1[C:2]([C:27]2[CH:26]=[C:25]([CH3:38])[C:24](=[O:39])[N:23]([CH3:22])[CH:28]=2)=[N:3][C:4]([CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])=[N:5][CH:6]=1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cn(C)c1=O
Reactant: CS(=O)(=O)Cc1ncc(Oc2ccc(F)cc2F)c(Cl)n1
Product: Cc1cc(-c2nc(CS(C)(=O)=O)ncc2Oc2ccc(F)cc2F)cn(C)c1=O

Procedure:
The title compound of Example 146, step 2 was reacted with 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one in a manner similar to Example 143, step 3 to give the title compound. 1H NMR (DMSO-d6, 400 MHz) δ 8.58 (d, J=2.0 Hz, 1H), 8.35 (s, 1H), 8.13 (s, 1H), 7.60-7.54 (m, 1H), 7.52-7.46 (m, 1H), 7.22-7.17 (m, 1H), 4.76 (s, 2H), 3.56 (s, 3H), 3.18 (s, 3H), 2.08 (s, 3H). LCMS: 422.1 (M+1)+
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]([C:18]2[CH:23]=[C:22]([Cl:24])[C:21]([NH2:25])=[CH:20][C:19]=2[O:26][CH3:27])=[O:17])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CO.C(OCC)C>[NH2:25][C:21]1[C:22]([Cl:24])=[CH:23][C:18]([C:16]([NH:15][CH2:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[O:17])=[C:19]([O:26][CH3:27])[CH:20]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
To a solution of N-tert-butyloxycarbonyl-4-(4-amino-5-chloro-2-methoxyphenylcarbonylaminomethyl)piperidine (500 mg, 1.26 mmol) in methanol solution (30 ml) was added an ethereal 1N hydrogen chloride solution (12.6 ml, 12.6 mmol). The solution was heated at 50° C. The reaction mixture became heterogeneous within 5 min. After 1.5 h, the reaction mixture was concentrated to give a white solid which was suspended in diethylether and filtered to give 4-(4-amino-5-chloro-2-methoxyphenylcarbonylaminomethyl)piperidine as a bis-hydrochloride salt (433 mg).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[N:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:22][C:23]1[CH:27]=[CH:26][N:25]([CH2:28][C:29]([CH3:32])([OH:31])[CH3:30])[N:24]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[N:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[C:8]([NH:22][C:23]2[CH:27]=[CH:26][N:25]([CH2:28][C:29]([OH:31])([CH3:30])[CH3:32])[N:24]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: O=C(O)C(CC1CCCC1)n1ncc2ccccc2c1=O
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc3ccccc3c2=O)n1
Yield: 11 %

Procedure:
Using the method described in Example 83, Step 3,3-cyclopentyl-2-(1-oxo-1H-phthalazin-2-yl)-propionic acid (as prepared in Example 83, Step 2) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(1-oxo-1H-phthalazin-2-yl)-propionamide as a white solid (48 mg, 11%); ES+-HRMS m/e calcd for C23H29N5O3 [M+H+] 319.1223 found 319.1223. 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.03 (s, 6H), 1.04-1.17 (m, 1H), 1.24-1.72 (m, 8H), 1.93-2.10 (m, 1H), 2.21-2.35 (m, 1H), 3.86 (s, 2H), 4.64 (s, 1H), 5.61 (dd, J=10.7, 4.1 Hz, 1H), 6.39 (d, J=2.1 Hz, 1H), 7.50 (d, J=2.1 Hz, 1H), 7.79-7.91 (m, 1H), 7.91-7.98 (m, 2H), 8.24 (d, J=7.5 Hz, 1H), 8.48 (s, 1H), 10.66 (s, 1H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[F:11].C([O-])([O-])=O.[K+].[K+].[NH:18]1[CH:22]=[CH:21][CH:20]=[CH:19]1>CS(C)=O.O>[F:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:18]1[CH:22]=[CH:21][CH:20]=[CH:19]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: c1cc[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(-n2cccc2)c(F)c1
Temperature: 90 °C
Yield: 97 %

Procedure:
To a solution of 1,2-difluoro-4-nitrobenzene (1.59 g, 10 mmol) in DMSO (15 mL) were added K2CO3 (3.04 g, 22 mmol) and pyrrole (0.74 g, 11 mmol) with stirring. The reaction mixture was heated at 90° C. for 18 h, and cooled to rt. The mixture was diluted with water (50 mL), filtered and the filter cake was dried to give the title compound as a yellow solid (2.00 g, 97%).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[N:7][NH:8]2)=[CH:4][C:3]=1[F:17].[CH:18]1([NH:21][C:22](=[O:39])[C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[C:25](B3OC(C)(C)C(C)(C)O3)[CH:24]=2)[CH2:20][CH2:19]1.C(=O)([O-])O.[Na+]>C(O)(C)C.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>[CH:18]1([NH:21][C:22](=[O:39])[C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([C:2]3[CH:10]=[C:9]4[C:5]([C:6]([C:11]5[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=5)=[N:7][NH:8]4)=[CH:4][C:3]=3[F:17])[CH:24]=2)[CH2:19][CH2:20]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Fc1cc2c(-c3ccncc3)n[nH]c2cc1Br
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: CC(C)O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1cc2[nH]nc(-c3ccncc3)c2cc1F
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 36.7 %

Procedure:
A suspension of 6-bromo-5-fluoro-3-(4-pyridinyl)-1H-indazole (Intermediate 4, 20 mg), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (21 mg), tetrakis(triphenylphosphine)palladium(0) (2 mg) and aqueous sodium hydrogen carbonate (1M, 1 ml) in isopropanol (2 ml) was stirred in a microwave oven at 150° C. for 15 min. The mixture was partitioned between water and ethyl acetate and the organic layer was washed with water and brine, dried using a hydrophobic filter tube and concentrated under vacuum. The residue was purified on an SPE cartridge (silica, 5 g) eluting with cyclohexane:ethyl acetate (1:1 to 1:4) to give the title compound as a white solid (9.72 mg).
Reaction SMILES: Cl.[CH3:2][C:3]1[NH:4][C:5]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:6]([CH2:8][CH3:9])[CH:7]=1.[CH3:15][CH:16]1OC(C)OC(C)O1>C(OC(=O)C)(=O)C>[CH3:2][C:3]1[NH:4][C:5]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:6]([CH2:8][CH3:9])[C:7]=1[CH2:15][CH3:16]
Reactant: CC1OC(C)OC(C)O1
Reactant: CCOC(=O)c1[nH]c(C)cc1CC
Agent: Cl
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1[nH]c(C)c(CC)c1CC
Reaction time: 0.5 h
Yield: 20 %

Procedure:
Acetic anhydride (20 ml) was stirred into 5 ml of concentrated hydrochloric acid with cooling. 2-Methyl-4-ethyl-5-carbethoxypyrrole (0.004 mol), paraldehyde (0.008 mol), and zinc amalgam (20 mesh, 10 g) were added at 25° C. and the mixture was stirred 1/2 h. The solution was decanted into 200 ml of water, this was made alkaline with ammonia and the crude product was filtered off. It was purified by sublimation, m.p. 76°-77° C. (lit. 75° C.). Yield 20%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].[Br:11]Br>C(O)(=O)C>[Br:11][C:8]1[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[NH2:7]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: BrBr
Solvent: CC(=O)O
Product: Nc1cc([N+](=O)[O-])ccc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
To a solution of 3-nitroaniline (0.5 g, 3.6 mmol) in 10 ml acetic acid added bromine (0.2 ml, 4.0 mmol) and stirred at 0° C. for 1 hour. The solution was filtered after recovering to room temperature to obtain 2-bromo-5-nitrobenzenamine (0.32 g, 40%) as a powder. A solution of 2-bromo-5-nitrobenzenamine (0.4 g, 1.8 mmol), sodium hydroxide (0.14 g, 3.6 mmol) and benzoyl chloride (0.24 ml, 2.0 mmol) in 20 ml THF was stirred for 2 hours in icy water bath. The reaction was quenched and washed with water (3×20 ml). The mixture was dried over anhydrous sodium sulfate. The crude N-(2-bromo-5-nitrophenyl)benzamide (0.3 g, 50%) was obtained after evaporation of the solvents. 1H NMR (500 MHz, CDCl3) δ (ppm) 7.65 (m, 2H), 7.68 (m, 1H), 7.80 (d, J=8.8 Hz, 1H), 7.94 (dd, J=8.8, 2.7 Hz, 1H), 8.00 (m, 2H), 8.62 (s, 1H), 9.55 (d, J=2.7 Hz, 1H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N:6]([CH2:9][C:10]([C:13]1[C:18]([F:19])=[CH:17][N:16]=[C:15]([Br:20])[CH:14]=1)([OH:12])[CH3:11])=[N+:7]=[N-:8].CCN(CC)CC>C(Cl)Cl>[N:6]([CH2:9][C:10]([O:12][S:2]([CH3:1])(=[O:4])=[O:3])([C:13]1[C:18]([F:19])=[CH:17][N:16]=[C:15]([Br:20])[CH:14]=1)[CH3:11])=[N+:7]=[N-:8]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)(CN=[N+]=[N-])c1cc(Br)ncc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(CN=[N+]=[N-])(OS(C)(=O)=O)c1cc(Br)ncc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
At 0° C., methanesulfonyl chloride (2.04 ml, 3.00 g, 26.20 mmol) was dropwise added to a solution of 1-azido-2-(2-bromo-5-fluoro-pyridin-4-yl)-propan-2-ol (6.00 g, 21.81 mmol) and NEt3 (3.65 ml, 2.65 g, 26.2 mmol) in DCM (200 ml). The reaction mixture was stirred at 0° C. for 1 h, then for another 1 h at 0° C. to rt. The reaction mixture was quenched with 1M aq. NaHCO3 soln. and diluted with DCM. The phases were separated and the aq. phase was twice reextracted with DCM. The combined org. phases were dried over Na2SO4, filtered and concentrated. HPLC purification (Alltech Grom Saphir 65 Si 10 μM column, 250×50 mm, gradient n-heptane:EtOAc 0-1.6 min 85:15, 1.6-16 min 0:100, 16-21.2 min 0:100, flow 100 ml/min, detection 254 nm) yielded the title compound as well as recovered starting material that could be reacted again according to the above procedure. HPLC RtH4=0.96 min; ESIMS: 353, 355 [(M+H)+]; 1H NMR (400 MHz, CDCl3): b 8.28 (d, 1H), 7.56 (d, 1H), 4.08 (d, 1H), 3.82 (d, 1H), 3.22 (s, 3H), 2.13 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17]C(=O)OC(C)(C)C)=[CH:13][CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[CH:4][N:3]=1>ClCCl>[NH2:17][C:14]1[CH:13]=[CH:12][C:11]([C:8]2[C:7]3[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[C:6]=3[S:10][CH:9]=2)=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2csc3c(-c4ccncc4)cnc(N)c23)cc1
Solvent: ClCCl
Product: Nc1ccc(-c2csc3c(-c4ccncc4)cnc(N)c23)cc1
Yield: 129 %

Procedure:
A solution of Example 121A (0.11 g, 0.263 mmol) in TEA (3 mL) and dichloromethane (1 mL) was stirred at room temperature for 30 minutes and concentrated under a stream of nitrogen. The residue was triturated from ethyl acetate/hexanes to provide 108 mg of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 5.66 (s, 2H), 6.78 (d, J=8.14 Hz, 2H), 6.97 (s, 2H), 7.20 (d, J=8.48 Hz, 2H), 7.75 (s, 1H), 7.91 (d, J=6.44 Hz, 2H), 8.19 (s, 1H), 8.83 (d, J=6.44 Hz, 2H); MS (ESI(+)) m/e 319 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[S:13][C:12]([CH2:20][CH2:21][CH2:22][NH:23][C:24]#[N:25])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]([C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[N:10]=1.Cl.[CH3:32][O:33][NH2:34].C(N(CC)CC)C>CCO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[S:13][C:12]([CH2:20][CH2:21][CH2:22][NH:23]/[C:24](/[NH2:25])=[N:34]\[O:33][CH3:32])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]([C:26](=[O:30])[CH:27]([CH3:28])[CH3:29])[N:10]=1
Reactant: CON
Reactant: CC(C)C(=O)N1N=C(c2cc(F)ccc2F)SC1(CCCNC#N)c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CO/N=C(/N)NCCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(=O)C(C)C
Temperature: 70 °C
Yield: 36.6 %

Procedure:
Crude (3-(5-(2,5-difluorophenyl)-3-isobutyryl-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propyl)cyanamide (35 mg, 0.08168 mmol) was transferred to a sealed tube in 3 mL of EtOH. Methoxyamine hydrochloride (170.5 mg, 2.042 mmol) and triethylamine (0.2846 ml, 2.042 mmol) were then added and the reaction heated to 70° C. for 18 hours. An additional 50 eq. of methoxyamine hydrochloride was added along with 50 equivalents of TEA. The reaction was then heated for 24 hours. The reaction was concentrated in vacuo, and the salts washed with ethyl acetate. The filtrate was then concentrated in vacuo, and the residue was purified by flash column chromatography (5-10% MeOH/CH2Cl2), to afford the desired product (14.2 mg, 36% yield) as a clear oil. MS ESI (+) m/z 476 (M+E) detected; 1H NMR (400 MHz, CDCl3) δ 7.52 (m, 1H), 7.38 (m, 4H), 7.13 (ms 3H), 3.73 (s, 3H), 3.54 (m, 1H), 3.38 (m, 4H), 2.50 (m, 1H), 2.13 (m, 1H), 1.64 (m, 1H), 1.19 (d, J=7.2 Hz, 6H).