Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Mg]Br.[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:20]([CH:21]=[O:22])=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][N:17]=2)[N:12]=1>C1COCC1>[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:20]([CH:21]([OH:22])[CH3:1])=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][N:17]=2)[N:12]=1
Reactant: O=Cc1cc2ncccc2nc1-c1ccccc1F
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)c1cc2ncccc2nc1-c1ccccc1F

Procedure:
Methyl magnesium bromide (2M in diethyl ether, 2.38 mL, and 4.76 mmol) was added dropwise to the solution of 2-(2-fluorophenyl)-1,5-naphthyridine-3-carbaldehyde (600 mg, 4.76 mmol) in THF (60 mL) at −0° C. After completion of reaction, the reaction mixture was quenched with saturated NH4Cl solution and ethyl acetate, and then filtered through Celite™. The organic layer was separated and the aqueous layer was back extracted with ethyl acetate. The organic layers were combined and dried over anhydrous Na2SO4 and concentrated under reduced pressure to give an oily mass. The oily mass was then purified by silica gel column chromatography using 30% of ethyl acetate and hexane as eluent to give 1-(2-(2-fluorophenyl)-1,5-naphthyridin-3-yl)ethanol as a yellow oil: 1H-NMR (CDCl3) δ: 1.3 (s, 3H), 5.0 (brs, 1H), 7.7-7.2 (m, 5H), 8.4 (d, 1H), 8.8 (s, 1H), 9.0 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[C:16]([CH3:25])=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][C:34]([CH2:39][OH:40])([CH2:37][OH:38])[CH2:35][OH:36].FC(F)(F)C(O)=O.[OH-].[Na+]>O.CN(C)C=O>[OH:36][CH2:35][C:34]([CH2:39][OH:40])([CH2:33][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:14][C:15]3[C:16]([CH3:25])=[N:17][C:18]4[C:23]([CH:24]=3)=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:2][CH3:1])[CH2:37][OH:38]
Reactant: OCC(CO)(CO)CBr
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCC(CO)(CO)CO
Temperature: 80 °C
Reaction time: 8 h
Yield: 20.7 %

Procedure:
N,N-Dimethylformamide (1.5 ml) was added to 6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-ol (compound 352) (50 mg), potassium carbonate (62 mg), and 2-bromomethyl-2-hydroxymethyl-propane-1,3-diol (90 mg), and the mixture was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was dissolved in dichloromethane (3 ml) to prepare a solution. Trifluoroacetic acid (3 ml) was added dropwise to the solution at 0° C., and the mixture was then stirred at room temperature for 3 hr. The reaction solution was made alkaline by the addition of a 1 N aqueous sodium hydroxide solution and was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (14 mg, yield 21%).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26]OCC2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN([CH2:41][C:42]3C=CC=[CH:44][C:43]=3Cl)C=2N=1)(C)(C)C.C1(N)CCCCC1>>[C:1]([C:5]1[N:6]=[C:7]([NH:22][CH:27]2[CH2:26][CH2:44][CH2:43][CH2:42][CH2:41]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Solvent: NC1CCCCC1
Product: CC(C)(C)c1nc(NC2CCCCC2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and cyclohexane-amine and isolated as light-yellow solid (3.8 mg, 20%). MS(m/e): 399.4 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([Cl:15])[CH:9]=2)[N:5]=[C:4]2[CH2:16][CH2:17][CH2:18][C:3]=12.[CH2:19]([O:21][C:22](=[O:31])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1)[CH3:20]>>[Cl:15][C:10]1[CH:9]=[C:8]([C:6]2[N:5]=[C:4]3[CH2:16][CH2:17][CH2:18][C:3]3=[C:2]([NH:30][C:27]3[CH:26]=[CH:25][C:24]([CH2:23][C:22]([O:21][CH2:19][CH3:20])=[O:31])=[CH:29][CH:28]=3)[CH:7]=2)[CH:13]=[C:12]([F:14])[CH:11]=1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: Fc1cc(Cl)cc(-c2cc(Cl)c3c(n2)CCC3)c1
Product: CCOC(=O)Cc1ccc(Nc2cc(-c3cc(F)cc(Cl)c3)nc3c2CCC3)cc1
Yield: 56.2 %

Procedure:
Following General Procedure B2, 4-chloro-2-(3-chloro-5-fluorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.100 g, 0.36 mmol) was reacted with 4-aminophenylacetic acid ethyl ester (0.096 g, 0.53 mmol) to afford the title compound (0.086 g, 87%) as a yellow oil. MW=424.90. 1H NMR (CD3OD, 300 MHz) δ 7.54 (s, 1H), 7.43-7.34 (m, 1H), 7.31 (s, 1H), 7.28 (s, 1H), 7.25-7.13 (m, 3H), 7.10-7.06 (m, 1H), 5.48 (s, 1H), 4.21-4.07 (m, 2H), 3.69 (s, 2H), 2.98 (t, J=7.6 Hz, 2H), 2.86 (t, J=7.6 Hz, 2H), 2.17 (quin, J=7.6, 2H), 1.37-1.17 (m, 3H); APCI MS m/z 425 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([Cl:9])=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.C[C:11]([N:13](C)C)=O>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[NH2:8][C:5]1[CH:4]=[C:3]([Cl:9])[C:2]([C:11]#[N:13])=[CH:7][N:6]=1
Reactant: Nc1cc(Cl)c(Br)cn1
Reactant: CC(=O)N(C)C
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Product: N#Cc1cnc(N)cc1Cl
Temperature: 70 °C
Reaction time: 16 h

Procedure:
5-bromo-4-chloropyridin-2-amine (500 mg, 2.41 mmol), zinc cyanide (297 mg, 2.53 mmol), zinc (31.5 mg, 0.482 mmol), Pd2(dba)3 (221 mg, 0.241 mmol), dppf (267 mg, 0.482 mmol) and DMA (20 ml) were charged into a flask under argon. The reaction mixture was stirred at 70° C. for 16 h. The reaction mixture was diluted in EtOAc and washed with sat. NaHCO3 (2×) and brine. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by normal phase chromatography (24 g silica gel cartridge, heptanes/EtOAc 100:0 to 58:42) to give the title compound as a beige solid. (UPLC-MS 1) tR 0.57 min; ESI-MS 154.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH:8][CH3:9])=[CH:6][CH:7]=1.[Cl:11][CH2:12][C:13](O)=O>>[Cl:11][CH2:12][C:13]1[N:8]([CH3:9])[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[N:10]=1
Reactant: O=C(O)CCl
Reactant: CNc1ccc(F)cc1N
Product: Cn1c(CCl)nc2cc(F)ccc21
Yield: 7.8 %

Procedure:
The title compound was prepared in accordance with the general method of Example 191(C), from 4-fluoro-N1-methylbenzene-1,2-diamine (2.5 g, 17.84 mmol) and 2-chloroacetic acid (2.50 g, 27 mmol). The crude residue was purified over silicagel chromatography (prepacked 70 g silicagel column, Cyclohexane/AcOEt: 60/40 as eluent) to afford 277 mg of 2-(chloromethyl)-5-fluoro-1-methyl-1H-benzo[d]imidazole (Yield: 8%) as a semi-solid.
Reaction SMILES: [CH:1]12[C:9](=[O:10])[NH:8][C:7](=[O:11])[CH:2]1[CH2:3][CH:4]=[CH:5][CH2:6]2.C(N(CC)CC)C.[C:19](Cl)(=[O:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].Cl.C(N(CC)CC)C>CCC(Cl)Cl>[C:19]([N:8]1[C:7](=[O:11])[CH:2]2[CH2:3][CH:4]=[CH:5][CH2:6][CH:1]2[C:9]1=[O:10])(=[O:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: O=C1NC(=O)C2CC=CCC12
Agent: CCC(Cl)Cl
Agent: Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCC(=O)N1C(=O)C2CC=CCC2C1=O
Reaction time: 0.17 h

Procedure:
A solution of 4-cyclohexene-1,2-dicarboximide (151g) and triethylamine (300 mls) in dichloropropane (900 mls) was maintained at a temperature of 50° C during the addition thereto over a period of 10 minutes, with constant stirring, of a solution of stearoyl chloride (302.5g) in a dichloropropane (300 mls). The mixture was stirred at 50° C for a further period of 10 minutes during which time triethylamine hydrochloride precipitated out, and was then filtered hot. The filtered precipitate was then washed with small portions of hot dichloropropane and the washings were combined with the filtrate. The solvent from the combined washings and filtrate was then evaporated off in a rotary evaporator to yield solid N-stearoyl-4-cyclohexene-1,2-dicarboximide, which was recrystallised from 60° - 80° petroleum ether.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:20]=[C:19]([CH3:21])[C:13]2[N:14]=[C:15]([NH2:18])[N:16]=[N:17][C:12]=2[CH:11]=1.Br[C:23]1[CH:24]=[C:25]([S:29][CH2:30][CH2:31][N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:26]=[CH:27][CH:28]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[K+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:20]=[C:19]([CH3:21])[C:13]2[N:14]=[C:15]([NH:18][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([S:29][CH2:30][CH2:31][N:32]4[CH2:33][CH2:34][CH2:35][CH2:36]4)[CH:24]=3)[N:16]=[N:17][C:12]=2[CH:11]=1
Reactant: COc1ccc(Cl)c(-c2cc(C)c3nc(N)nnc3c2)c1
Reactant: Brc1cccc(SCCN2CCCC2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: COc1ccc(Cl)c(-c2cc(C)c3nc(Nc4cccc(SCCN5CCCC5)c4)nnc3c2)c1
Temperature: 100 °C
Yield: 74 %

Procedure:
7-(2-chloro-5-methoxy-phenyl)-5-methyl-benzo[1,2,4]triazin-3-ylamine (1.0 equiv., 083 mmol), 1-[2-(3-bromo-phenylsulfanyl)-ethyl]-pyrrolidine (1.5 equiv., 1.25 mmol), Xantphos (0.1 equiv., 0.084 mmol), palladium acetate (0.05 equiv., 0.042 mmol), and potassium-tert-butoxide (2.0 equiv., 1.66 mmol) were dissolved in 10 mL of dioxane, and argon was bubbled through the solution. The reaction was run under an argon blanket while refluxing at 100° C. for 18 h. The reaction was then cooled to room temperature, filtered to remove inorganics, extracted using EtOAc with saturated NaHCO3 and brine, dried over Na2SO4, and concentrated under reduced pressure. A crude material was precipitated using 1:5 (v/v) EtOAc/hexanes to afford a bright orange solid (311.8 mg, 74% yield). Rf=0.48.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:16]3[N:17]=[C:18]([NH2:20])[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].Br[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:16]3[N:17]=[C:18]([NH:20][C:22]4[CH:23]=[CH:24][C:25]([N:28]5[CH2:29][CH2:30][O:31][CH2:32][CH2:33]5)=[CH:26][CH:27]=4)[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1cccc(-c2cccc3nc(N)nn23)c1
Reactant: Brc1ccc(N2CCOCC2)cc1
Product: CS(=O)(=O)c1cccc(-c2cccc3nc(Nc4ccc(N5CCOCC5)cc4)nn23)c1
Yield: 25.2 %

Procedure:
[5-(3-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(4-morpholin-4-yl-phenyl)-amine was prepared from 5-(3-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (137 mg, 0.475 mmol) and 4-(4-bromo-phenyl)-morpholine (138 mg, 0.57 mmol) in a manner analogous to Example 77 to yield [5-(3-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(4-morpholin-4-yl-phenyl)-amine (53.8 mg, 24%) as a yellow powder following purification on a 40 g Isco silica gel column using 0-5% methanol in dichloromethane as an eluent. MP=163° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.38 (s, 1H), 8.76 (m, 1H), 8.35 (d, J=8.0 Hz, 1H), 8.11 (d, J=8.0 Hz, 1H), 7.88 (t, J=15.5 Hz, 8.5 Hz, 1H), 7.67 (m, 1H), 7.57 (m, 3H), 7.32 (d, J=7.5 Hz, 1H), 6.88 (d, J=8.50 Hz, 2H), 3.73 (m, 4H), 3.33 (s, 3H), 2.99 (m, 4H). MS=450 (MH)+.
Reaction SMILES: [H][H].CO.[ClH:5].[N+:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[B:15]([OH:17])[OH:16])([O-])=[O:7]>[Pd]>[ClH:5].[OH:7][NH:6][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[B:15]([OH:17])[OH:16]
Reactant: O=[N+]([O-])c1ccccc1B(O)O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: ONc1ccccc1B(O)O
Temperature: 24 °C

Procedure:
Into a Parr shaker hydrogenation apparatus fitted with a hydrogen source and Parr bomb was charged 0.1 gm of a palladium on carbon hydrogenation catalyst obtained from Aldrich Chemical Co. under the trade designation Palladium on Carbon, 100 mL of methanol containing 1 equivalent of hydrochloric acid, and 0.8 gm of 2-nitrophenyl-boronic acid prepared in accordance with the procedure described in W. Leaman and J. R. Johnson, J. Am. Chem. Soc., 1931, 53, 711. The apparatus was sealed and was flushed with hydrogen gas and maintained under 42 psi of hydrogen at a temperature of 24° C. for 4 hr. Solids were then removed by filtration, and the filtrate was vacuum concentrated. The tan, hygroscopic solid product (mp 185°-187° C. (dec)) was isolated by filtration:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[CH:4][CH:3]=1.[CH:10]([CH:12]=O)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([N:7]=1)=[N:8][CH:10]=[CH:12][N:9]=2
Reactant: Nc1ccc(Cl)nc1N
Reactant: O=CC=O
Solvent: C1CCOC1
Product: Clc1ccc2nccnc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
6-chloro-2,3-pyridinediamine (Intermediate 4.1) (1 g, 6.96 mmol, 1 eq.) was dissolved in THF (15 mL). Glyoxal (0.84 mL, 18.1 mmol, 2.5 eq.) was added and reaction mixture stirred at rt for 2 hours. Reaction was monitored by RP-HPLC. THF was evaporated, residue re-dissolved in ethyl acetate (30 mL). Organic phases washed twice with saturated Na2CO3, dried with magnesium sulfate and evaporated under vacuum to give 1.15 g of the expected compound as a white solid (Intermediate 4.2). Amount: 1.15 g; Yield: 100%; Formula: C7H4N3Cl; HPLC Purity: 98%; HPLC (H2O TFA 0.1%-ACN TFA 0.05%): Rt (min); Area %=1.2 min; 98%; 1H NMR (CDCl3) δ 9.0 (s, 1H), 8.88 (s, 1H), 8.36 (d, 1H, J=8 Hz), 7.67 (d, 1H, J=8 Hz); LC-MS: M/Z ESI: Rt (min) 0.68 min, 167.0 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[C:4]2[C:8]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)=[N:7][O:6][CH:5]=2)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:21]([OH:23])[CH3:22]>>[CH2:21]([O:23][C:5](=[O:6])[C:4]1[C:3]([CH2:1][CH3:2])=[CH:11][C:10]([N+:12]([O-:14])=[O:13])=[CH:9][C:8]=1[NH2:7])[CH3:22]
Reactant: CCO
Reactant: CCc1cc([N+](=O)[O-])cc2nocc12
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1c(N)cc([N+](=O)[O-])cc1CC

Procedure:
4-ethyl-6-nitro anthranil (2 g) was refluxed for three hours in ethanol with potassium carbonate. The reaction mixture was cooled, filtered and evaporated to a dark oily solid which was dissolved in ethyl acetate and dried. The residue was re-dissolved in methylene chloride and columned on silica gel using 15% ethyl acetate-petroleum ether. The residue from the filtrate was recrystallized from methylene chloride-petroleum ether to give 1.9 g ethyl-2-amino-6-ethyl-4-nitrobenzoate, m.p. 68°-70° C., IR: 3490 cm, 3380 cm, 3080 cm, 2980 cm, 1690 cm, 1620 cm, 1515 cm, 1350 cm.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([CH2:9][NH:10][C:11]1[C:16]([N+:17]([O-])=O)=[CH:15][CH:14]=[CH:13][N:12]=1)[CH2:6][CH2:7][CH3:8])[CH3:2]>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([CH2:9][NH:10][C:11]1[C:16]([NH2:17])=[CH:15][CH:14]=[CH:13][N:12]=1)[CH2:6][CH2:7][CH3:8])[CH3:2]
Reactant: CCCC(CNc1ncccc1[N+](=O)[O-])C(=O)OCC
Agent: [Pd]
Solvent: CCO
Product: CCCC(CNc1ncccc1N)C(=O)OCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
To a solution of 2-[(3-nitro-pyridin-2-ylamino)-methyl]-pentanoic acid ethyl ester (90 mg, 0.32 mmol) in EtOH (5 mL) was added Pd/C (20 mg). The reaction mixture was de-gassed using house vacuum and saturated with H2. The reaction mixture was stirred at room temperature for 18 hours. The mixture was filtered through a pad of celite and the filtrate was concentrated to afford 70 mg (87%) of the desired product which was used for the next reaction without further purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]=[CH:17][CH:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([N:36]2[CH:40]=[C:39](B3OC(C)(C)C(C)(C)O3)[CH:38]=[N:37]2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C([O-])([O-])=O.[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[C:23]([O:27][C:28]([N:30]1[CH2:31][CH2:32][CH:33]([N:36]2[CH:40]=[C:39]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8]([CH2:11][C:12]5[CH:13]=[C:14]6[C:19](=[CH:20][C:21]=5[F:22])[N:18]=[CH:17][CH:16]=[CH:15]6)=[CH:9][N:10]=4)[N:7]=3)[CH:38]=[N:37]2)[CH2:34][CH2:35]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: Fc1cc2ncccc2cc1Cc1cnc2ccc(Cl)nn12
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3ccc4ncc(Cc5cc6cccnc6cc5F)n4n3)cn2)CC1
Temperature: 90 °C

Procedure:
A microwave tube was charged with 6-(6-chloro-imidazo[1,2-b]pyridazin-3-ylmethyl)-7-fluoro-quinoline (Stage 180.2, 500 mg, 1.599 mmol), 4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (prepared as described in published patent application WO 2007/066185 p. 9 & 10; 905 mg, 2.398 mmol), Pd(PPh3)2Cl2 (56 mg), 2 M K2CO3 (2.158 mL) and DME (5 mL) and was heated at 90° C. for 2 h under stirring. The RM was extracted with EtOAc and aqueous NaHCO3. The organic layer was dried and concentrated in vacuo. The reside was dried under vacuum (12 mbar) for 3 days to afford the title compound (tR 4.5 min (conditions 3), MH+=528)
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][CH:12]2[CH2:14][CH2:13]2)[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[NH2:15][C:16]1[CH:24]=[C:23]2[C:19]([CH:20]=[N:21][N:22]2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(O)(C)C>[CH:12]1([NH:11][C:4]2[C:5]3[O:10][CH:9]=[CH:8][C:6]=3[N:7]=[C:2]([NH:15][C:16]3[CH:24]=[C:23]4[C:19]([CH:20]=[N:21][N:22]4[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:18][CH:17]=3)[N:3]=2)[CH2:14][CH2:13]1
Reactant: Clc1nc(NC2CC2)c2occc2n1
Reactant: CC(C)(C)OC(=O)n1ncc2ccc(N)cc21
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)n1ncc2ccc(Nc3nc(NC4CC4)c4occc4n3)cc21
Temperature: 85 °C
Yield: 48 %

Procedure:
To a flask was added 2-chloro-N-cyclopropylfuro[3,2-d]pyrimidin-4-amine (10.5 g, 50.1 mmol, Example #3, Step C), tert-butyl 6-amino-1H-indazole-1-carboxylate (14.02 g, 60.1 mmol, Frontier), K2CO3 (8.31 g, 60.1 mmol) and t-BuOH (334 mL). The reaction vessel was purged under vacuum and vented with N2 three times. To the mixture was added Pd2dba3 (2.75 g, 3.01 mmol) and X-Phos (2.87 g, 6.01 mmol). The reaction vessel was purged under vacuum and vented with N2. The mixture was heated to about 85° C. for about 3 days. The mixture was diluted with EtOAc (1000 mL) and washed with water (1000 mL). The organic layer was dried with MgSO4, filtered through a pad of Celite® and concentrated in vacuo. The residue was purified by column chromatography (300 g silica gel, DCM/MeOH 1:0 to 10:1) to give a solid. The material was further purified by column chromatography (300 g silica gel, DCM/EtOAc 1:0 to 0:1) to give tert-butyl 6-(4-(cyclopropylamino)furo[3,2-d]pyrimidin-2-ylamino)-1H-indazole-1-carboxylate (9.78 g, 48%): LC/MS (Table 2, Method u) Rt=1.48 min; MS m/z: 407 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:42]=[CH:41][CH:40]=[CH:39][C:3]=1[C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH3:12])[S:8][C:7]=1[N:13]1[C:17]([CH2:18][NH:19][C:20]([C:22]2[N:23]([CH2:31][C:32]([O:34]CC)=[O:33])[C:24]3[C:29]([CH:30]=2)=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])=[N:16][N:15]=[C:14]1[CH2:37][OH:38])=[O:5].[OH-].[Na+]>>[Cl:1][C:2]1[CH:42]=[CH:41][CH:40]=[CH:39][C:3]=1[C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH3:12])[S:8][C:7]=1[N:13]1[C:17]([CH2:18][NH:19][C:20]([C:22]2[N:23]([CH2:31][C:32]([OH:34])=[O:33])[C:24]3[C:29]([CH:30]=2)=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])=[N:16][N:15]=[C:14]1[CH2:37][OH:38])=[O:5]
Reactant: CCOC(=O)Cn1c(C(=O)NCc2nnc(CO)n2-c2sc(CC)cc2C(=O)c2ccccc2Cl)cc2ccccc21
Agent: [Na+]
Agent: [OH-]
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(CO)nnc2CNC(=O)c2cc3ccccc3n2CC(=O)O)s1

Procedure:
Ethyl 2-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-3-hydroxymethyl[1,2,4]triazol-5-ylmethylcarbamoyl)indole-1-acetate is subjected to alkali hydrolysis using a 2M aqueous sodium hydroxide solution to give 2-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-3-hydroxymethyl[1,2,4]triazol-5-ylmethylcarbamoyl)indole-1-acetic acid.
Reaction SMILES: [CH2:1]([N:8]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26](CC4OCCO4)[CH:25]=3)=[CH:19][CH:18]=2)=[C:15]2[C:10]([C:11]([C:36]([F:39])([F:38])[F:37])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.C[C:58](C)=[O:59]>>[CH2:1]([N:8]1[C:16]([C:17]2[CH:18]=[CH:19][C:20]([O:23][C:24]3[CH:25]=[C:26]([CH:27]=[CH:28][CH:29]=3)[CH:58]=[O:59])=[CH:21][CH:22]=2)=[C:15]2[C:10]([C:11]([C:36]([F:37])([F:38])[F:39])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1cccc2c(-c3ccc(Oc4cccc(CC5OCCO5)c4)cc3)n(Cc3ccccc3)nc12
Reactant: CC(C)=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: O=Cc1cccc(Oc2ccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3ccccc3)cc2)c1

Procedure:
2-benzyl-3-[4-(3-[1,3]dioxolan-2-ylmethyl-phenoxy)-phenyl]-7-trifluoromethyl-2H-indazole (14 mg, 0.0264 mmol) was treated with 6.6 mg PPTS in 1.5 ml acetone under reflux for 2 hrs. The reaction mixture was extracted with NaHCO3 and CH2Cl2. The combined organic phases were dried, evaporated and the crude material was purified on a chromatotron using a gradient changing from 1:99 (EtOAc/heptane) to 3:7 (EtOAc/heptane) to afford 5 mg of analytically pure product.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)OC(C)(C)C)=[C:4]([NH:16][C:17]2[N:22]=[C:21]([S:23][C:24]#[N:25])[C:20]([N+:26]([O-:28])=[O:27])=[CH:19][N:18]=2)[CH:3]=1.[C:29]([OH:35])([C:31]([F:34])([F:33])[F:32])=[O:30]>C(Cl)Cl>[F:32][C:7]1[CH:6]=[C:5]([NH2:8])[C:4]([NH:16][C:17]2[N:22]=[C:21]([S:23][C:24]#[N:25])[C:20]([N+:26]([O-:28])=[O:27])=[CH:19][N:18]=2)=[CH:3][CH:2]=1.[C:29]([OH:35])([C:31]([F:34])([F:33])[F:32])=[O:30]
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)cc1Nc1ncc([N+](=O)[O-])c(SC#N)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CSc1nc(Nc2ccc(F)cc2N)ncc1[N+](=O)[O-]

Procedure:
tert-Butyl 4-fluoro-2-(5-nitro-4-thiocyanatopyrimidin-2-ylamino)phenylcarbamate (4.06 g) was dissolved in 30% TFA in DCM (50 mL) and stirred until no starting material remained (90 min). The reaction solvents were removed, to yield crude 5-fluoro-N′-(5-nitro-4-thiocyanatopyrimidin-2-yl)benzene-1,2-diamine (MH+=306) as a TFA salt that was used immediately as such in the next step.